Turner 2014

BBAMCR-17280; No.
of pages: 20; 4C: 3, 4, 5, 6, 8, 10

Biochimica et Biophysica Acta xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbamcr
1 Cytokines and chemokines: At the crossroads of cell signalling and

2 inflammatory disease
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3Q1 Mark D. Turner a,⁎, Belinda Nedjai b, Tara Hurst a, Daniel J. Pennington c
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4Q2 a
Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, United Kingdom
5Q3 b
Leukocyte Biology Section, National Heart and Lung Institute, Imperial College, South Kensington, London , United Kingdom
6 c
Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, E1 2AT, United Kingdom
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7 a r t i c l e i n f o a b s t r a c t
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8 Article history: Inflammation occurs as a result of exposure of tissues and organs to harmful stimuli such as microbial pathogens, 19
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Received 19 February 2014 irritants, or toxic cellular components. The primary physical manifestations of inflammation are redness, swell- 20
10 Received in revised form 22 May 2014 ing, heat, pain, and loss of function to the affected area. These processes involve the major cells of the immune 21
11 Accepted 23 May 2014
system, including monocytes, macrophages, neutrophils, basophils, dendritic cells, mast cells, T-cells, and B- 22
12 Available online xxxx
cells. However, examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes
D 23
13 Keywords:
in any given lesion. That is, the inflammatory process is regulated in such a way as to ensure that the appropriate 24
14 Innate immunity leukocytes are recruited. These events are in turn controlled by a host of extracellular molecular regulators, in- 25
15 cluding members of the cytokine and chemokine families that mediate both immune cell recruitment and com- 26
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Tumour necrosis factor
16 Interleukin plex intracellular signalling control mechanisms that characterise inflammation. This review will focus on the 27
17 Interferon role of the main cytokines, chemokines, and their receptors in the pathophysiology of auto-inflammatory disor- 28
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18 Chemotaxis ders, pro-inflammatory disorders, and neurological disorders involving inflammation. 29

30 © 2014 Published by Elsevier B.V.
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33
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35 1. Introduction will focus on the role of the main cytokine and chemokine cell signalling 56
molecules, and how disruption of these pathways triggers inflammatory 57
36 The last 50 years has witnessed a rapid growth in research into in- disorders. 58
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37 flammatory diseases. This advance of information has led researchers

38 and physicians to begin to redefine many diseases including heart dis- 2. Cytokine signalling 59
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39 ease, Alzheimer's disease, type 1 diabetes, type 2 diabetes and obesity

40 as inflammatory disorders. Much of this new view has come from re- Cytokines are key modulators of inflammation, participating in acute 60
41 search showing that people with chronic inflammatory diseases have and chronic inflammation via a complex and sometimes seemingly con- 61
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42 elevated blood levels of C-reactive protein and other markers of inflam- tradictory network of interactions. Better understanding of how these 62
43 mation [1,2]. Relatively minor inflammatory disorders, such as injuries pathways are regulated helps facilitate more accurate identification of 63
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44 or allergies, can also set the stage for more serious chronic inflammatory agents mediating inflammation and the treatment of inflammatory dis- 64
45 diseases, and many inflammatory disorders actually develop as clusters. eases. It is possible to classify cytokines based on the nature of the im- 65
46 Inflammation is controlled by a host of extracellular mediators and mune response (Table 1), with individual cytokines also performing 66
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47 regulators, including cytokines, growth factors, eicosanoids (prosta- specific roles dependent upon cell type and location (Table 2). Key 67
48 glandins, etc), complement and peptides. In fact, it is the discovery of pro-inflammatory cytokines include interleukin-1 (IL-1), IL-6 and tu- 68
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49 many of these mediators over the past 20 years that has increased our mour necrosis factor (TNFα), all of which signal via the type I cytokine 69
50 understanding of the regulation of the inflammatory process whilst, at receptors that are structurally divergent from other cytokine receptor 70
51 the same time, revealing its complexity. These extracellular events are types. By contrast, the critical pro-inflammatory chemokine, IL-8, sig- 71
52 matched by equally complex intracellular signalling control mecha- nals via G protein-coupled receptors (GPCRs) (Fig. 1). The major pro- 72
53 nisms, governed by the ability of cells to assemble and disassemble a inflammatory cytokines, their receptor-mediated signalling pathways, 73
54 complex array of signalling pathways as they move from inactive to and their contribution to human disease are discussed below. 74
55 dedicated roles within the inflammatory response site. This review
2.1. Interleukin-1 (IL-1) 75
⁎ Corresponding author at: School of Science and Technology, Nottingham Trent

University, Clifton Lane, Nottingham NG11 8NS, United Kingdom. Tel.: +44 115 848 3113. The IL-1 family now includes 11 members: IL-1α, IL-1β, the IL-1 re- 76
E-mail address: mark.turner@ntu.ac.uk (M.D. Turner). ceptor antagonist [IL-1Ra], IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, 77
http://dx.doi.org/10.1016/j.bbamcr.2014.05.014
0167-4889/© 2014 Published by Elsevier B.V.
Please cite this article as: M.D. Turner, et al., Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease, Biochim.
Biophys. Acta (2014), http://dx.doi.org/10.1016/j.bbamcr.2014.05.014
2 M.D. Turner et al. / Biochimica et Biophysica Acta xxx (2014) xxx–xxx
t1:1 Table 1
t1:2 Classification of cytokines by immune response. Cytokines can be broadly grouped based on whether they act on cells of the adaptive immune response, or promote or inhibit
t1:3 inflammation. Further, they can be classified based on the receptors used for signalling.
t1:4 Family Members
t1:5 Adaptive immunity Common γ chain receptor ligands IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
t1:6 Common β chain (CD131) receptor ligands IL-3, IL-5, GM-CSF
t1:7 Shared IL-2β chain (CD122) IL-2, IL-15
t1:8 Shared receptors IL-13 (IL-13R–IL-4R complex)
t1:9 TSLP (TSLPR–IL-7R complex)
t1:10 Pro-inflammatory signalling IL-1 IL-1α, IL-1β, IL-1ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-1Hy2
t1:11 IL-6 IL-6, IL-11, IL-31, CNTF, CT-1, LIF, OPN, OSM
t1:12 TNFα TNFα, TNFβ, BAFF, APRIL
t1:13 IL-17 IL-17A-F, IL-25 (IL-17E)
t1:14 Type I IFN IFNα, IFNβ, IFNω, IFNκ, Limitin
t1:15 Type II IFN IFNγ
t1:16 Type III IFN IFNλ1 (IL-29), IFNλ2 (IL-28A), IFNλ3 (IL-28B)
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t1:17 Anti-inflammatory signalling IL-12 IL-12, IL-23, IL-27, IL-35
t1:18 IL-10 IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29
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t1:19 Abbreviations: CNTF, ciliary neurotrophic factor; CT-1, cardiotrophin-1; GM-CSF, granulocyte macrophage-colony stimulating factor; IFN, interferon; LIF, leukaemia inhibitory factor; OPN,
t1:20 osteopontin; OSM, oncostatin M; TNFα, tumour necrosis factor α; TSLP, thymic stromal lymphopoietin.
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78 IL-37 and IL-1Hy2 [3]. These cytokines are expressed by numerous cell macrophages throughout the body [5]. Whereas the expression of IL- 90
79 types, including macrophages and monocytes, and comprise both pro- 1α is constitutive in many cell types, by contrast IL-1β expression is 91
80 and anti-inflammatory members [3]. Of these, IL-1β is a potent pro- induced mainly in response to microbial molecules, although it can 92
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81 inflammatory cytokine that was originally identified as an endogenous also stimulate its own expression [6]. Stimulation of pattern recognition 93
82 pyrogen. Further, IL-1β and has been found to have a stimulatory effect receptors (PRRs) including Toll-like receptors (TLRs) and NOD-like 94
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83 on CD4+ T cells and to promote differentiation into the T helper cell lin- receptors (NLLs) can be induced both by viral and microbial molecules. 95
84 eages, particularly T helper (Th17) cells and a non-classically derived This can then lead to the induction of IL-1β expression [7,8]. Members 96
85 Th1 cell lineage [4]. Given its central role in mediating a wide array of of the IL-1 family, including IL-1β, are typically synthesised as precur-
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86 inflammatory signalling responses, we will mainly discuss the actions sors without a secretory sequence. IL-1β must therefore be cleaved in 98
87 of the pro-inflammatory cytokine, IL-1β, in this section. order to generate active cytokine [9] and this is performed by the IL- 99
88 IL-1α and IL-1β are synthesised by multiple cell types including 1-converting enzyme (ICE), or caspase-1, which is contained within a 100
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89 monocytes, macrophages, neutrophils, hepatocytes, and tissue specialised intracellular complex termed the inflammasome [6]. In 101
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t2:1 Table 2
t2:2 Functions of cytokines. Cytokine action, defined by target cell and primary function.
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t2:3 Main sources Target cell Major function
Cytokines IL-1 Macrophages, B cells, DCs B cells, NK cells, T-cells Pyrogenic, pro-inflammatory, proliferation and differentia-
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t2:4 tion, BM cell proliferation

t2:5 IL-2 T cells Activated T and B cells, NK cells Proliferation and activation
t2:6 IL-3 T cells Stem cells Hematopoietic precursor proliferation and differentiation
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t2:7 NK cells
IL-4 Th cells B cells, T cells macrophages Proliferation of B and cytotoxic T cells, enhances MHC class II
t2:8 expression, stimulates IgG and IgE production
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IL-5 Th cells Eosinophils, B-cells Proliferation and maturation, stimulates IgA and IgM
t2:9 production
t2:10 IL-6 Th cells, macrophages, fibroblasts Activated B-cells, plasma cells Differentiation into plasma cells
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t2:11 IgG production

t2:12 IL-7 BM stromal cells, epithelial cells Stem cells B and T cell growth factor
t2:13 IL-8 Macrophages Neutrophils Chemotaxis, pro-inflammatory
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t2:14 IL-9 T cell T cell Growth and proliferation

IL-10 T cell B cells, macrophages Inhibits cytokine production and mononuclear cell function,
t2:15 anti-inflammatory
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t2:16 IL-11 BM stromal cells B cells Differentiation, induces acute phase proteins
t2:17 IL-12 T cells NK cells Activates NK cells
t2:18 TNFα Macrophages Macrophages Phagocyte cell activation, endotoxic shock
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t2:19 Monocytes Tumour cells Tumour cytotoxicity, cachexia

TNFβ T-cells Phagocytes, tumour cells Chemotactic, phagocytosis, oncostatic, induces other
t2:20 cytokines
t2:21 Interferons IFNβ Fibroblasts Various Anti-viral, anti-proliferative
IFNγ T-cells Various Anti-viral, macrophage activation, increases neutrophil and
t2:22 monocyte function, MHC-I and -II expression on cells
t2:23 TNFα Macrophages Macrophages Phagocyte cell activation, endotoxic shock
t2:24 Monocytes Tumour cells Tumour cytotoxicity, cachexia
TNFβ T cells Phagocytes, tumour cells Chemotactic, phagocytosis, oncostatic, induces other
t2:25 cytokines
t2:26 Colony stimulating factors G-CSF Fibroblasts, endothelium Stem cells in BM Granulocyte production
t2:27 GM-CSF T cells, macrophages, fibroblasts Stem cells Granulocyte, monocyte, eosinophil production
t2:28 M-CSF Fibroblast, endothelium Stem cells Monocyte production and activation
t2:29 Erythropoietin Fibroblast, endothelium Stem cells Red blood cell production
Others TGFβ T cells and B cells Activated T and B cells Inhibit T and B cell proliferation, inhibit haematopoiesis,
t2:30 promote wound healing
t2:31 Abbreviations: BM, bone marrow; DCs, dendritic cells; G-CSF, granulocyte-colony stimulating factors; M-CSF, macrophage colony stimulating factor; Th, T helper cells.
M.D. Turner et al. / Biochimica et Biophysica Acta xxx (2014) xxx–xxx 3
Cytokines Chemokines
IL-6
TNFα GAGs IL-8
IL-1β IL-8
IL-8
FIII
IGDs
CRDs module
Receptor
Types
D gp130 gp130 α γ
TIR
TIR
D β
F
IL-1R/IL-1AcP TNFR1 or TNFR2 IL-6R CXCR1 or CXCR2
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Fig. 1. Cytokines, chemokines and their receptors. Cytokines signal via oligomers of single-pass, type I transmembrane receptors, with distinct extracellular domains for ligand binding and
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intracellular domains that allow signal transduction. The receptor for IL-1 is a complex of IL-1R1 and the IL-1RAcP formed following ligand binding to the extracellular immunoglobulin
domains (IGDs); intracellular signalling is mediated via the Toll/IL-1R (TIR) domain. Trimeric TNFα binds to the cysteine-rich domains (CRDs) of the pre-assembled trimmers of the TNF
receptor (TNFR) and signalling is mediated via the receptor's death domain (DD). Finally, the IL-6R is a multimeric structure with IL-6R chains complexed with gp130. The ligand-binding
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region is within the fibronectin III (FIII) modules of the IL-6R chains but signal transduction is via the associated gp130 molecules. Chemokine signalling occurs via activation of the seven
transmembrane G protein-coupled receptors (GPCRs). IL-8 binds to the extracellular face of either CXCR1 or CXCR2, triggering a conformational change that results in the activation of the
G-proteins. Abbreviations: FIII module, fibronectin III module; GAGs, glycosaminoglyans.
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102 contrast, IL-1α is active in both its precursor and mature forms but isoforms of IL-1Ra are intracellular, it has been hypothesised that the 143
103 typically remains in the nucleus, the cytoplasm, or on the cell mem- critical site of IL-1Ra could be a cytosolic location where it could block
D 144
104 brane [9]. Despite these differences, IL-1α and IL-1β have similar affin- IL-1 expression or signalling by altering mRNA stability [12]. Thus, 145
105 ities for the two IL-1 receptors, IL-1R1 and IL-1R2. The heterodimeric while IL-1Ra acts as a natural suppressor of inflammation, on its own 146
106 complex of IL-1R1 and the IL-1R accessory protein (IL-1RAcP) consti- it might be insufficient to quell IL-1 signalling and its function could 147
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107 tutes the functional receptor for IL-1 [10]. Normally, IL-1β binds first be more complex, involving intracellular modulation of IL-1. 148
108 to IL-1R1 on the surface of target cells and then the IL-1RAcP is recruit-
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109 ed, thus forming a trimolecular signalling complex (Fig. 2). IL-1R 2.2. Tumour necrosis factor (TNFα) 149
110 belongs to the IL-1R/TLR superfamily due to the presence a conserved
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111 cytoplasmic Toll/IL-1R (TIR) domain [10]. Following ligand binding The term tumour necrosis factor was initially conferred to two mol- 150
112 the adaptor molecule, MyD88, interacts with IL-1R1 via its TIR domain ecules, TNFα a monocyte-derived tumour necrosis factor, and TNFβ a 151
113 [10]. Signal transduction leads to activation of both mitogen-activated lymphocyte-derived tumour necrosis factor, Tumour necrosis factor 152
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114 protein kinases (MAPKs) and the transcription factor NF-κB, thereby (TNFα) was initially identified in the 1970s as an endotoxin-induced 153
115 resulting in pro-inflammatory cytokine expression. In addition to serum factor responsible for the necrosis of certain tumours in vivo 154
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116 this classical signalling pathway, there is also evidence that regulat- and in vitro [16]. Subsequently TNFα was isolated [17] and its gene 155
117 ed intramembrane proteolysis of IL-1R1 generates both a soluble cloned [18]. It is a potent inflammatory mediator that is central to the 156
118 ectodomain and an intracellular domain, with the latter directly modu- inflammatory action of the innate immune system, including induction 157
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119 lating MAPK activation [11]. Thus, proteolytic processing of cytosolic re- of cytokine production, activation or expression of adhesion molecules, 158
120 ceptors could contribute to signalling by a non-canonical mechanism. and growth stimulation [19–22]. It stimulates the proliferation of nor- 159
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121 The IL-1 family also includes members that have an inhibitory role, mal cells, exerts cytolytic or cytostatic activity against tumour cells, 160
122 enabling them to suppress signalling and thereby limit inflammatory and causes inflammatory, antiviral, and immunoregulatory effects 161
123 response. Firstly, IL-1R2 has a minimal intracellular domain that renders [23]. TNFα has also been shown to perform a number of additional func- 162
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124 it inactive, and thus signalling is not induced following ligand binding. tions linked with lipid metabolism, coagulation, insulin resistance, and 163
125 IL-1R2 is therefore thought to act as a decoy receptor, sequestering IL- endothelial function. Indeed, it has been shown to be one of the most 164
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126 1 in an anti-inflammatory mechanism [6]. Secondly, The IL-1R antago- important and pleiotropic cytokines mediating inflammatory and im- 165
127 nist (IL-1Ra) is able to bind to the IL-1R1 and, in doing so, prevents mune responses. 166
128 the recruitment of IL-1RAcP [3], thereby inhibiting signal transduction. TNFα is the prototypic member of the TNF superfamily of type II 167
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129 IL-1Ra is expressed as one of four different isoforms, generated by alter- transmembrance proteins that includes 30 receptors and 19 associated 168
130 native splicing, including one secreted form (sIL-1Ra) and three cytosol- ligands with diverse functions in cell differentiation, inflammation, 169
131 ic forms [12]. It is secreted by a number of cell types, including immunity and apoptosis [24]. It is primarily secreted from activated 170
132 neutrophils, macrophages, monocytes and hepatocytes [12]. The sIL- macrophages, although it may also be secreted by other cell types in- 171
133 1Ra is one of the acute phase proteins secreted by the liver in response cluding monocytes, T cells, mast cells, NK cells, keratinocytes, fibroblasts 172
134 to inflammatory stimuli [12]. Its absence is deleterious, with IL-1Ra- and neurons [25]. TNFα is synthesised as a transmembrane precursor 173
135 deficient mice being prone to the development of various inflammatory protein (mTNFα) with a molecular mass of 26 kDa [25], after which it 174
136 disorders and more susceptible to the effects of experimental immune is transported via the rough endoplasmic reticulum (RER), Golgi com- 175
137 challenges [13,14]. Despite this finding, the efficacy of IL-1Ra is thought plex and the recycling endosome to the cell surface [26]. The monomers 176
138 to be much lower relative to that of agonist, resulting in the need for a of TNFα associate at the plasma membrane as non-covalent trimers [27, 177
139 up to 1000-fold excess IL-1RA in order to inhibit IL-1 signalling [15]. 28] prior to being cleaved by the metalloprotease, TNFα converting en- 178
140 This is potentially due to the high level of IL-1R1 expression on most zyme (TACE or ADAM17) [29]. Cleavage by TACE results in the produc- 179
141 cells to which IL-1Ra may bind, while Il-1 itself need only bind a few re- tion of 17 kDa soluble TNFα (sTNFα) ectodomain and it is trimers of 180
142 ceptors to trigger signal transduction [15]. Given that three of the sTNFα that constitute the potent ligand that activates TNF receptors 181
IL-1
IL-1R IL-1RAcP
TIR
TIR
Plasma membrane
MyD88
IRAK2
Ub
Ub
TRAF6 TRAF6
F
TAB1
TAK1
TAB2
O
MKK3/6 IKK
O
P P
P P
I B
JNK p38
NF- B
p65 p50
R
Gene Transcription
P
CHOP ATF2
AP1
p65 p50
Pro-inflammatory cytokine D
Nucleus expression
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Fig. 2. IL-1 signal transduction to NF-κB activation. IL-1 binds to the IL-1R, which associates with the IL-1RAcP at the cell surface, and signals via the TIR adaptor, MyD88, through homotypic
TIR-TIR interactions. Subsequently, IL-1R associated kinases (IRAKs) are recruited to the receptor/MyD88 complex. Activated IRAKs promote TNFR-associated factor 6 (TRAF6)
polyubiquitination via lysine 63 linkages. The polyubiquitinated TRAF6 interacts with TAK1 in complex with TAB1 and TAB2, ultimately leading to the phosphorylation of IκBα and its
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dissociation from NF-κB subunits. The phosphorylated IκBα is subsequently ubiquitinated for degradation by the proteasome. The phosphorylated p65/p50 heterodimer translocates
to the nucleus, where it binds to response elements in NF-kB-dependent genes and leads to the induction of pro-inflammatory gene expression. In addition, the activation of TAK1/
TAB1/TAB2 leads to the phosphorylation and activation of the mitogen-activated protein kinases (MAPKs), JNK and p38. These kinases then phosphorylate and activate transcription
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factors, thereby inducing the expression of pro-inflammatory genes. Abbreviations: IKK, IκB kinase; IκBα, inhibitor of κB; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor
κB; TAB1, TAK1 binding protein 1; TAB2, TAK1 binding protein 2; TAK1, transforming growth factorβ-activated kinase 1.
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182 [25]. Following TACE cleavage, the membrane stub is proteolytically interaction with associated adaptor molecules (Fig. 3). Recruitment of 209
183 processed by the signal peptide peptidases (SPPLs) SPPL2a and SPPL2b TRADD to TNFR1 is required for both signalling pathways [34]. Subse- 210
184 [30]. This cleavage produces an intracellular domain (ICD) that translo- quently, one of two complexes is formed, either at the cell surface (com- 211
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185 cates to the nucleus and induces pro-inflammatory cytokine signalling, plex I) or following internalisation (complex II) [35]. The formation of 212
186 particularly the expression of IL-12 [30]. Thus, the precursor TNFα mol- complex I requires TNFR-associated factor 2 (TRAF2) and receptor- 213
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187 ecule is subjected to multiple cleavage events to release potent modula- interacting protein (RIP), leading to kinase cascades that trigger pro- 214
188 tors of inflammation. inflammatory gene expression. Alternatively, should the first complex 215
189 The molecular actions of extracellular sTNFα and mTNFα typically fail to signal, Complex II is formed to induce apoptosis [35]. In Complex 216
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190 occur through binding to one of two receptors: TNFR1 (TNFRSF1A, II, proteolysis and internalisation of the receptor results in the recruit- 217
191 p55TNFR1, p60, CD120a) and TNFR2 (TNFRSF1B, p75TNFR, p80 or ment of FADD and pro-caspase-8 to form the death-inducing signalling 218
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192 CD120b) [25]. The receptors are expressed on different cell types, with complex [35]. 219
193 TNFR1 being widely expressed, while TNFR2 is expressed predominant- Unlike TNFR1, TNFR2 lacks a DD. However it does possess an intra- 220
194 ly on leukocytes and endothelial cells [31]. The two TNFRs have been cellular TRAF-binding motif, by which it too has the potential to modu- 221
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195 reported to mediate distinct biological effects. Knockout mice for late inflammatory status. The distinct cytoplasmic domains could 222
196 TNFRSF1A (TNFR1) are resistant to endotoxic shock, but they are much account for the differential signalling of the receptors by sTNFα and 223
197 more susceptible than either TNFRSF1B (TNFR2) knockouts or wild mTNFα. It was found that mTNFα was a more potent activator of 224
198 type controls to challenge with Listeria monocytogenes [32]. Thus, pro- TNFR2 than sTNFα and induced distinct biological outcomes [36]. Fur- 225
199 inflammatory effects of TNFα appear to be mediated predominantly ther, activation of TNFR1 was found to stimulate NF-κB expression to a 226
200 through TNFR1. significantly greater extent than TNFR2 [37]. Finally, Scatchard analysis 227
201 Both TNFR1 and TNFR2 are single transmembrane glycoproteins of ligand binding to TNFR1 and TNFR2 found that the former had a 228
202 with 28% homology in their extracellular domains [27]. Common fea- higher affinity for TNFα [38]. Thus, TNFR1 is considered to be the 229
203 tures in this region include four cysteine-rich domains (CRDs), each of more important of the two receptors for the activation of pro- 230
204 which comprises three cysteine-cysteine disulphide bonds, and a pre- inflammatory signalling pathways. 231
205 ligand binding assembly domain (PLAD) involved in trimerisation of Importantly, several cytokine receptors have been found to undergo 232
206 the receptor [33]. Importantly, the receptors differ by the presence of ectodomain shedding by membrane-localised proteolytic enzymes. This 233
207 an intracellular death domain (DD) at the carboxyl-end of TNFR1 [27] process releases a soluble form of the receptor that can have a biological 234
208 that is able to drive either apoptosis or inflammation through role such as limiting cytokine availability to other cells, and akin to that 235
Soluble
TNFα
Membrane-bound
Ectodomain
TNFα
shedding
TNFR1
TNFR2
MMP
Plasma membrane
D
Internalisation and D
further proteolysis Complex I
TRADD
TRAF2
FADD
Complex II
MEKK1 RIP IKK
F
Pro-caspase 8
O
NEMO
MKK7 MKK3/6 Ub Proteasomal
DISC degradation
P
I B
P
O
Caspase 8 I B
JNK p38 p65 p50
NF- B
R
Caspase 3
Gene IL-1
Transcription
P
CHOP ATF2 TNFα Inflammation
AP1 p65 p50 and cell
Apoptosis
CAMs survival
Pro-inflammatory cytokine D
Nucleus expression I B
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Fig. 3. Signalling via the TNF receptors 1 and 2. Following TNFα binding to TNFR1, the receptor undergoes ectodomain shedding and internalisation, events which are linked to the intra-
cellular signalling cascade. Ectodomain shedding is mediated by matrix metalloproteases resident in the plasma membrane and is followed by further proteolysis. Signalling following
receptor internalisation is thought to pro-apoptotic signalling via the formation of Complex II (TRADD/FADD/Pro-Caspase-8). Alternatively, the recruitment of adaptor molecules to the
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cell surface prior to internalisation is thought to lead to the formation of Complex I (TRADD/TRAF2/RIP), followed by mitogen-activated protein kinase (MAPK) cascades leading to tran-
scription factor activation. JNK activates the AP1 heterodimer of c-Jun and Fos, while p38 activates numerous transcription factors; only CHOP and ATF2 are shown for clarity. In addition,
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Complex I signalling leads to IKK activation, which results in the phosphorylation and degradation of IκBα by the ubiquitin–proteasome system. The activated NF-κB heterodimer of p65/
p50 can then migrate to the nucleus, bind to response elements and induce the expression of pro-inflammatory genes. Importantly, the outcome of the Complex I signalling pathways
favour pro-inflammatory cytokine expression and cell survival. That said, it is well known that the MAPK JNK can also contribute to the induction of cell death. Abbreviations: CAMs,
cellular adhesion molecules; DISC, death-inducing signalling complex; FADD, Fas-associated death domain protein; JNK, Jun N-terminal kinase; MMP, matrix metalloprotease; RIP,
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receptor-interacting protein; TRADD, TNFR1-associated death domain protein; TRAF2, TNFR-associated protein 2;.
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236 discussed above for IL-1. Both TNFR1 and TNFR2 are cleaved by TACE stimulating factor (HSF), B-cell stimulatory factor 2 (BSF-2), and B cell 260
237 following ligand binding, terminating the signal by decreasing availabil- differentiation factor (BCDF). The discovery and cloning of BSF-2 in 261
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238 ity of plasma membrane receptors as well as releasing soluble TNFR to 1986 [49] was followed by recognition of the fact that these diverse ac- 262
239 sequester free TNFα [39,40]. The production of soluble TNFR1 has tivities were due to a single cytokine, renamed IL-6 [45]. The gene 263
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240 been described in inflammatory conditions [41]. As mentioned above, encoding IL-6 was mapped to chromosome 7 in humans and it encodes 264
241 TNFR1 forms a trimer prior to ligand binding, which could lead to acti- a glycoprotein that ranges in mass from 21 to 28 kDa, depending on the 265
242 vation of signal transduction by bringing together the DD of the recep- extent of post-translational modification [50]. 266
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243 tors. This can be suppressed by the association of the silencer of death IL-6 signals through a ligand-binding IL-6 receptor (IL-6R) α chain 267
244 domains (SODD) with the TNFR DD [42]. Following TNFα binding, (gp80, CD126) and the signal-transducing component gp130 (CD130) 268
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245 SODD disassociates from TNFR, allowing adaptor molecules to be re- [43]. CD130 is the common signal transducer for several cytokines in 269
246 cruited [42]. Thus, there are instrinsic mechanisms to limit TNFR signal- the IL-6 family and is ubiquitously expressed [51], whereas the IL-6R 270
247 ling in the absence of ligand, as well as to curtail signalling following subunit is typically restricted to lymphocytes and hepatocytes [52]. Fol- 271
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248 ligand binding. lowing IL-6 binding, the signal is transduced by the gp130 chains to 272
activate JAK-STAT signalling (Fig. 4). This signalling pathway leads to 273
249 2.3. Interleukin-6 (IL-6) phosphorylation of STAT3, a member of the wider STAT family of 274
transcription factors which are associated with cytokine signalling 275
250 The interleukin-6 (IL-6) family are pleiotropic cytokines that include (Table 3), and results in STAT3 nuclear translocation and IL-6- 276
251 the members IL-6 itself and IL-11 [43]. IL-6 is expressed by an array of responsive gene expression. In addition to the membrane-bound recep- 277
252 cells, including mononuclear phagocytes, T cells, B cells, fibroblasts, en- tor, a soluble form of IL-6R (sIL-6R) is generated by TACE-mediated 278
253 dothelial cells, keratinocytes, hepatocytes, and bone marrow cells [44]. cleavage and can capture circulating IL-6 and make it available to bind 279
254 IL-6 is involved in haematopoiesis, and is critical in the final maturation and activate gp130 via a process of trans-signalling [43]. In contrast, a 280
255 of B-cells into antibody-producing plasma cells [45], T cell activation, soluble form of gp130 functions as an anti-inflammatory decoy recep- 281
256 differentiation and regulation of Th2 and Treg phenotypes [46,47]. It is tor, blocking sIL-6R trans-signalling [53]. More recently, the caspase- 282
257 also important in the secretion of acute phase proteins by the liver mediated cleavage of gp130 has been found to produce a small, 283
258 [48], which it does in cooperation with IL-1 [6]. Previous names for IL- 18 kDa C-terminal fragment and to thereby terminate IL-6 signal trans- 284
259 6 illustrate some of these biological activities, including hepatocyte- duction, possibly leading to apoptosis [54]. Thus, a common theme of 285
IL-6
IL-6R/gp130 complex
JAK JAK
P
P
P P
Stat3 Stat3
F
Stat3 P
Stat3
O
O
P Gene
Stat3 P Transcription
R
Stat3
P
Nucleus
D
Fig. 4. IL-6 signalling pathway. The cytokine binds to the FIII domains of the IL-6R chains, ultimately activating signal transduction via the gp130 proteins. This leads to recruitment of janus
kinases (JAKs) to the receptor, which phosphorylate the receptor and themselves. This leads to STAT3 phosphorylation and dimerization. Phosphorylated STAT3 dimers translocate to the
E
nucleus and bind to an IFNγ activation site (GAS) in responsive genes. This leads to the transcription of pro-inflammatory genes and intracellular adhesion molecules.
T
286 cytokine signalling involves the proteolytic cleavage of the receptor to have since been described [55]. To date, 44 chemokines and 23 chemo- 301
287 modulate signalling or produce a soluble ectodomain to bind to circulat- kine receptors have been identified in the human genome [57]. It is the 302
C
288 ing ligands. expression of particular chemokines, receptors, and adhesion molecules 303
that contribute to the selective migration and tissue specificity of leuko- 304
289 3. Chemokine signalling cytes. Chemokines are a group of small (8–12 kDa) proteins that are 305
E
characterised by the presence of three to four conserved cysteine resi- 306

290 Pro-inflammatory chemokines are produced by cells primarily to re- dues. They can be subdivided into four families based on the positioning 307
R
291 cruit leukocytes to the sites of infection or injury. Chemokines induce of the N-terminal cysteine residues (Table 4). The C–X–C subfamily is 308
292 integrin expression, such as the β2-intergrin lymphocyte function–as- characterised by the separation of the first two cysteines by a variable 309
293 sociated antigen (LFA-1), in target leukocytes that act to arrest the amino acid, while in the C–C subfamily the cysteine residues are 310
R
294 rolling of these cells and favour diapedesis through the endothelium adjacent to each other. The majority of the known chemokines are 311
295 [55]. Although chemotaxis is the cardinal feature of chemokines, their contained in the CXC and C–C subfamilies but two additional chemokine 312
O
296 physiological role is more complex, with many having additional ho- subgroups have been described. The third group of chemokines (the C 313
297 meostatic or housekeeping functions in hematopoiesis, initiation of subfamily) lacks the first and third cysteines and thus possesses only a 314
298 adaptive immune responses and immune surveillance [56]. single cysteine residue in the conserved position. This subfamily includes 315
C
299 Initially chemokines were divided into groups based on having che- the lymphocyte-specific chemotactic peptide XCL1 (lymphotactin) [58]. 316
300 motactic or homeostatic function, but several dual-function chemokines A fourth subfamily (CX3C) has the two N-terminal cysteine residues sep- 317
N
arated by three variable amino acids [59]. In humans, this family has only 318
t3:1 Table 3
one member: CX3CL1 (fractalkine), which is unique in possessing a 319
t3:2 The STAT family of proteins in cytokine signalling. mucin-like glycosylated stalk that allows it to exist as a soluble or 320
U
membrane-bound chemokine [59]. 321

t3:3 STAT Cytokine signalling pathway
Chemokine signals are transduced through binding to members of 322
STAT1 IFNα/βa IFNγa Epidermal growth factor, platelet-derived growth the seven-transmembrane, G protein–coupled receptor (GPCR) super- 323
t3:4 factor, M-CSF, IL-6, IL-11
family [56], although there is also evidence that other effector pathways 324
t3:5 STAT2 IFNα/βa IFNλ
STAT3 IL-6 (IL-6 family cytokines, including IL-6, oncostatin M, and LIF) are possible [60]. There is heterogeneity in chemokine receptor expres- 325
trigger STAT3 though the gp130 receptor) IL-5, IL-10, epidermal sion in cells and they can form multiple complexes, such as the demon- 326
t3:6 growth factor, human growth factor stration that CXCR4 and CCR5 can heterodimerise when stimulated 327
t3:7 STAT4 IL-12 (essential endogenous mediator of TH1 differentiation) with their respective ligands [61]. The G proteins associate with the car- 328
t3:8 STAT5A and Prolactin IL-2, IL-3, IL-7, GM-CSF, erythropoietin, thrombopoietin
boxyl terminus of the receptor and signal-induced conformational 329
STAT5Bb
t3:9 STAT6 IL-4 (essential endogenous mediator of TH2 differentiation) changes activates G protein-mediated signalling [60]. In addition, 330
a
there are a number of decoy receptors for chemokines that are not 331
t3:10 IFNα/β signalling complex (interferon-stimulated gene factor 3) consists of trimers of
coupled to G proteins and so cannot signal, including: duffy antigen re- 332
STAT1 (alternatively spliced α [p91] or β [p84] peptides), STAT2, and the non-STAT pro-
tein p48. IFNγ signalling complex consists of dimers of STAT1. ceptor for chemokines (DARC), D6, and CCX-CKR [62]. Decoy chemo- 333
t3:11 b
Two distinct genes that are 90% identical. kine receptors are generally thought to play a role in dampening the 334
t4:1 Table 4 two general subgroups (ELR and non-ELR) based upon the presence or 350
t4:2 Chemokine families. The most common names for the human ligands are listed. ELR is a absence of the amino acid motif (Glu-Leu-Arg) immediately preceeding 351
t4:3 conserved amino acid motif (Glu-Leu-Arg) immediately preceding the first cysteine
t4:4 amino acid in the CXCL chemokine family.
the first cysteine [65]. The ELR-positive chemokines (CXCL1, CXCL2, 352
CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8/IL-8) are angiogenic and act 353
t4:5 Systematic name Receptor mainly through the CXCR2 receptor [66]. The ELR motif, along with 354
(common name)
the CXC residues, is required for receptor activation [66]. By contrast, 355
t4:6 CC chemokine/receptor family CCL1(I-309) CCR8, R11 the non-ELR chemokines (CXCL4, CXCL9, CXCL10, CXCL11 and 356
t4:7 CCL2 (MCP-1, MCAF) CCR2
CXCL17) are angiostatic and act mainly through the CXCR3B receptor 357
t4:8 CCL3 (MIP-1α/LD78α) CCR1, R5
t4:9 CCL3L1 (LD78β) CCR5 [67]. The exception to this is CXCL12, which is a non-ELR chemokine 358
t4:10 CCL4 (MIP-1β) CCR5 but is angiogenic and exerts its effects on the vasculature primarily by 359
t4:11 CCL4L1 CCR5 binding to CXCR4 and CXCR7 [68]. The role of chemokines thus extends 360
t4:12 CCL4L2 CCR5 beyond chemotaxis to include contributions to vascularisation and an- 361
t4:13 CCL5 (RANTES) CCR1, R3, R4, R5
giogenesis in cancer. 362
t4:14 CCL6 (C-10) CCR1, R2, R3
t4:15 CCL7 (MCP-3) CCR1, R2, R3 Chemokine release from cells can also trigger the destructive inva- 363
F
t4:16 CCL8 (MCP-2) CCR1, R2, R5, R11 sion of immune cells into essential tissues and organs. This occurs in 364
t4:17 CCL9 (MRP-2/MIP-1γ) CCR1 both type 1 and type 2 diabetes where glucotoxicity activates pancreatic 365
O
t4:18 CCL10 (MRP-2/MIP-1γ) CCR1
β-cell NLRP3 inflammasomes [69], thereby driving production and re- 366
t4:19 CCL11 (Eotaxin) CCR3
t4:20 CCL12 (MCP-5) CCR2 lease of IL-1β [70]. This then acts in an autocrine manner, binding the 367
t4:21 CCL13 (MCP-4) CCR1, R2, R3, R11 β-cell IL1R and triggering the activation of the transcription factor NF- 368
O
t4:22 CCL14 (HCC-1) CCR1 κB [70]. This results in the synthesis and release of a host of other cyto- 369
t4:23 CCL15 (HCC-2, Lkn-1) CCR1, R3 kines and chemokines from islet cells [71]. These molecules trigger infil- 370
t4:24 CCL16 (HCC-4, LEC) CCR1
R
tration of the pancreas by macrophages and other immune cells [72]. 371
t4:25 CCL17 (TARC) CCR4
t4:26 CCL18 (DC-CK1, PARC) Unknown Together this toxic cocktail of endogenous and immune cell released cy- 372
t4:27 CCL19 (MIP-3β, ELC) CCR7, R11 tokines results in the apoptotic destruction of insulin secreting β-cells 373
P
t4:28 CCL20 (MIP-3α, LARC) CCR6 [73,74]. 374
t4:29 CCL21 (6Ckine, SLC) CCR7, R11
t4:30 CCL22 (MDC, STCP-1) CCR4
t4:31 CCL23 (MPIF-1) CCR1 D
t4:32 CCL24 (MPIF-2, Eotaxin-2) CCR3 3.1. Interleukin-8 (IL-8) 375
t4:33 CCL25 (TECK) CCR9, R11
t4:34 CCL26 (Eotaxin-3) CCR3 Also known as CXCL8, IL-8 is one of the most widely studied 376
E
t4:35 CCL27 (CTACK, ILC) CCR2, R3, R10
chemokines and is a critical inflammatory mediator. It was originally 377
t4:36 CCL28 (MEC) CCR3, R10
t4:37 C chemokine/receptor family XCL1 (Lymphotactin) XCR1 identified for its role in chemoattraction of neutrophils, for which it 378
T
t4:38 XCL2 (SCM1-b) XCR1 was named neutrophil chemotactic factor (NCF) and neutrophil activat- 379
t4:39 CXC chemokine/receptor family CXCL1 (GROα, MGSA-α) CXCR2 N R1 ing protein (NAP-1) [75,76]. The IL-8 genomic structure was first 380
C
t4:40 CXCL2 (GROβ, MGSAβ) CXCR2

mapped in the late 1980s [77]. The IL-8 protein is 6–8 kDa in molecular 381
t4:41 CXCL3 (GROγ, MGSAγ) CXCR2
t4:42 CXCL4 (PF4) CXCR3
mass and belongs to a subdivision of the CXC chemokines [78]. It acts as 382
t4:43 an angiogenic factor in human microvascular endothelial cells [79]. The 383
E
CXCL4L1 (PF4V1) CRCR3

t4:44 CXCL5 (ENA-78) CXCR1, R2 main role of IL-8 in inflammation is in the recruitment of neutrophils 384
t4:45 CXCL6 (GCP-2) CXCR1, R2 [80], although it is also responsible for the chemotactic migration and 385
R
t4:46 CXCL7 (NAP-2) CXCR2

activation of monocytes, lymphocytes, basophils, and eosinophils at 386
t4:47 CXCL8 (IL-8) CXCR1, R2
t4:48 CXCL9 (Mig) CXCR3 sites of inflammation [75]. IL-8 can be found in either monomeric or di- 387
meric forms and both are required for neutrophil activation, albeit with 388
R
t4:49 CXCL10 (IP-10) CXCR3

t4:50 CXCL11 (I-TAC) CXCR3 distinct kinetics [81]. Further, the binding of dimers to glycosaminogly- 389
t4:51 CXCL12 (SDF-1α/β) CXCR4, R7 cans (GAGs) is more efficient and therefore facilitates binding to endo- 390
t4:52
O
CXCL13 (BLC, BCA-1) CXCR3, R5

t4:53 CXCL14 (BRAK, bolekine) Unknown
thelial cells, as well as binding to the CXCR1/2 on the neutrophils [81]. 391
t4:54 CXCL15 Unknown Indeed, heparin was found to be the only GAG associated with IL-8 to in- 392
t4:55 CXCL16 (SR-PSOX) CXCR6 duce neutrophil chemotaxis [82]. Although IL-8 can bind to both CXCR1 393
C
t4:56 CXCL17 (VCC1, DMC) Unknown and CXCR2, it has been found that chemotactic signalling is primarily via 394
t4:57 CX3C chemokine/receptor family CXCCL1 (Fractalkine) CR3CR1
CXCR1 [78,80]. Following binding to CXCR1 or CXCR2, a number of in- 395
N
tracellular signalling cascades are activated within the target cells to in- 396
duce chemotaxis and degranulation (Fig. 5). These cascades are initiated 397
335 immune response, leading to resolution of inflammation. However, primarily via the activation of intracellular G proteins, resulting in the 398
U
336 recently, this concept has been challenged by the finding that duffy dissociation of the proteins from the receptor and separation of the 399
337 antigen receptor for chemokines (DARC) can mediate chemokine Gα and Gβγ subunits. The G protein subunits then stimulate enzymes 400
338 transcytosis, leading to apical retention of the chemokine and enhanced (adenylate cyclase or phospholipase C) that can activate MAPK signal- 401
339 leukocyte migration across monolayers [62,63]. ling and alter gene expression to promote cell survival, proliferation 402
340 Chemokines perform a variety of functions aside from chemotaxis, and inflammation. Importantly, the production of 3,4,5-inositol triphos- 403
341 including T helper cell differentiation and function, as well as angiogen- phate (IP3) triggers the release of intracellular calcium stores that 404
342 esis. Chemokines can have direct effects on T cell differentiation through stimulate degranulation. Neutrophil granules contain several effector 405
343 direct interactions on the developing cell or indirectly by altering APC molecules, such as the antimicrobial proteins myeloperoxidase, 406
344 trafficking or cytokine secretion. For example, it was recently found defensins and lysozyme [83]. In addition, IL-8 signalling via MAPK and 407
345 that the chemokine receptor, CXCR3, was upregulated on CD4 + T phosphatidylinositol-3 kinase (PI3K) induces the expression of adhe- 408
346 cells and this was associated with cytokine expression and differentia- sion molecules such as the integrin, Mac-1, that are required for chemo- 409
347 tion of these cells to type 1 (Th1) cells [64]. An important role of the taxis [84]. Thus, IL-8 mediates the recruitment and activation of 410
348 chemokines is in angiogenesis, although this function lies with a sub- neutrophils via complex signalling mechanisms and extracellular adhe- 411
349 class of the CXC chemokines. The CXC chemokines can be divided into sion molecules. 412
Endothelial cell
IL-8 dimer
CXCR1 or CXCR2 Neutrophil, T cell
A
C
PLCβ
IP3 + DAG
cAMP
Gα
Gβ
GTP
Gα PKA
Ca2+ PKC γ
Degranulation γ
β
Ras
Rap1
F
c-Raf
b-Raf
O
MEK-1/2
O
P P P
ERK1 ERK2
R
P Gene
Transcription
P
Elk1/2
Nucleus
D
Fig. 5. IL-8 signalling pathway. IL-8 is thought to exist as monomers in the plasma but that local concentrations in the tissues favours dimer formation and these dimers are modified by the
E
addition of glycosaminoglycans (GAGs). The GAGs facilitate binding of IL-8 to endothelial cells; they can then bind to a slow progression of migrating lymphocytes. Binding of IL-8 to the
the chemokine receptors CXCR1 or CXCR2 leads to activation of the heterotrimeric G-proteins (Gα, β, γ). The Gα subunit in particular activates the membrane-bound adenylate cyclase
(AC), which generates cyclic AMP (cAMP) and cAMP can then activate protein kinase A (PKA). Alternatively, the Gβγ heterodimer can dissociate from the Gα subunit and stimulate phos-
T
pholipase β (PLCβ) activity, which cleaves phospholipids to produce inositol 3,4,5-triphosphate (IP3) and diacylglycerol (DAG). DAG activates PKC, which then induces MAPK activation,
whereas IP3 triggers the degranulation by stimulating the release of Ca2+ from intracellular stores.
C
413 4. Cytokines and chemokines in inflammation patients with rheumatoid arthritis, coincide with the recruitment of 442
E
monocytes and T cells into synovial tissues [95,96]. In addition, CCR5, 443
414 Several diseases have been described in which aberrant or excessive CCR6, CCR7, CXCR3, CXCR4 and CXCR5 have also been implicated in B- 444
R
415 signalling by cytokines contributes to pathogenesis [85]. For example, cell synovial cytokine production and activity [97]. Psoriasis pathophys- 445
416 up-regulation of IL-1 and IL-6 has been observed in a variety of chronic iology is also linked to chemokine-mediated inflammation and 446
417 inflammatory and autoimmune disorders such as type I diabetes, rheu-
R
418 matoid arthritis, lupus nephritis, psoriasis and systemic sclerosis

419 [86–90]. It is well established that TNFα is directly involved in the pa-
O
420 thology of several systemic diseases (Fig. 6), as well as affecting disease
Rheumatoid
421 pathology through more localised effect. Importantly, appropriate levels
arthritis
422 of TNFα are also essential to perform key homeostatic functions,
C
423 exerting a variety of effects on normal cell function, including cell prolif-
424 eration, necrosis and apoptosis [27]. TNFα serves a key function in
N
425 orchestrating the inflammatory response [31] that includes both sys-
426 temic and local responses. TNFα actions include triggering the vascular
427 endothelial cell expression of lipid mediators that promote tissue oede- Parkinson’s
TRAPS
U
428 ma, as well as leukocyte adhesion molecules that stimulate immune cell Disease
429 infiltration. For example, the early induction of chemokine expression TNFα
430 and lymphocyte infiltration in response to microbial infection is due
431 to the actions of TNFα [91]. A number of large studies have shown the
432 efficacy of anti-TNFα therapy in inflammatory diseases. Importantly, in-
433 sight into the central function of TNFα in synovial inflammation led to
434 the development of TNFα blockers, which have proven to be highly ef-
435 fective therapeutics [92]. Alzheimer’s Behçet’s
436 Specific chemokines and their receptors have also been found to be disease disease
437 elevated in the tissues of patients with inflammatory conditions
438 (Table 5). IL-8 can be detected in synovial fluid from patients with var-
439 ious inflammatory rheumatic diseases [93], and mucosal levels of IL-8
440 are elevated in patients with active ulcerative colitis [94]. Elevated levels Fig. 6. The central role of TNFα. TNFα expression is aberrant in numerous inflammatory
441 of CC chemokines, particularly CCL2, CCL3, and CCL5 in the joints of and neurodegenerative diseases.
t5:1 Table 5 Importantly, proteinuria is observed in FMF patients and is highly 499
t5:2 Chemokines and chemokine receptors implicated in inflammatory diseases. suggestive of amyloidosis. Secondary amyloidosis (AA) is the main 500
t5:3 Chemokine/chemokine receptor Disease and potentially lethal complication of the disease. In patients with phe- 501
notype II FMF, secondary amyloidosis (AA) is observed and patients typ- 502
t5:4 CXCR4 WHIM syndrome
t5:5 CX3CR1, CX3CL1, CXCL1, CXCL8, CXCR2, CCL2 Atherosclerosis ically have two mutations in the FMF-associated gene (Mefv). Recently, 503
t5:6 CCL2, CCL5, CCL7, CCL11, CXCL8 Asthma, allergic diseases a population study in Turkey identified 27 allelic variants among 22 504
t5:7 CCR5, CXCR3 Rheumatoid arthritis patients with phenotype II MEFV [109]. Most patients with overt clinical 505
disease bear two mutations of MEFV; however, it has been recently 506
emphasised that in a subset of patients, only one mutation can be 507
447 lymphocyte recruitment in the skin, such as the CXCR3 ligand-mediated detected [110]. Further to this, some heterozygotes displayed inflam- 508
448 infiltration of T cells [98]. The differential distribution of chemokine re- matory symptoms typical of FMF [111–113]. Given the traditional clas- 509
449 ceptors on different leukocyte types also provides a tool for determining sification of FMF as a recessive disorder, this finding is somewhat 510
450 the role of individual chemokines in particular diseases. Here, the con- surprising and the above findings suggest that FMF could be inherited 511
451 tribution of these bioactive molecules to inflammatory diseases and as a dominant trait, though with reduced penetrance. The presence of 512
F
452 therapeutic strategies for their modulation will be examined. multiple allelic variants further suggests that inheritance of FMF could 513
be due to more than one Mefv mutation. 514
O
The Mefv gene product, pyrin, is a member of the tripartite motif 515
453 5. Inflammatory disorders and therapeutic strategies
family (TRIM20) with a conserved C-terminal PRYSPRY domain in 516
which several of the common mutations observed in FMF are located 517
O
454 5.1. Auto-inflammatory disorders
[114]. It is hypothesised that wild-type pyrin acts as a suppressor of in- 518
flammation and that mutation of pyrin leads to a loss of suppression. 519
455 The relatively new category of auto-inflammatory disorders com-
R
Consistent with this hypothesis and the aforementioned elevation in in- 520
456 prises a group of inherited diseases of the innate immune system. The
flammation in patients, the knockout the Mefv gene locus in a mouse 521
457 core group consists of six disorders which are also known as hereditary
model and the consequent loss of pyrin expression resulted in elevated 522
458
P
recurrent fever syndromes. While auto-inflammatory disorders share
levels of IL-1 [115]. Thus, the complete loss of pyrin would result in the 523
459 similarities with autoimmune diseases, they represent a distinct catego-
absence of a normal inhibitor of inflammation. However, FMF is 524
460 ry of disorders that are characterised by intense episodes of inflamma-
characterised by an array of allelic variations that result in mutations 525
461 tion that result in fever, rash, or joint swelling. These diseases also D
in pyrin, rather than its complete absence. Thus, the symptoms of FMF 526
462 carry the risk of amyloidosis which results in a potentially fatal accumu-
are hypothesised to be due to these mutations rendering pyrin less ef- 527
463 lation of protein in organs.
fective at inhibiting inflammation, with a range of severity depending 528
E
464 The most prevalent auto-inflammatory disorder is Familial Mediterra-
upon the given mutation. However, the data do not rule out the hypoth- 529
465 nean fever (FMF), but several other such disorders have been described.
esis that some mutations in pyrin could result in a gain of function such 530
466 These disorders include: tumour necrosis factor receptor associated peri-
T
that the mutant pyrin could actively promote the pro-inflammatory 531
467 odic syndrome (TRAPS), mevalonate kinase deficiencies (MKD), severe
pathway or suppress the anti-inflammatory arm. A further aspect of 532
468 mevalonic aciduria (MA), moderate hyper immunoglobulin D and peri-
C
pyrin's biology could be important in this context, as all of the current 533
469 odic fever syndrome (HIDS), Muckle Wells syndrome (MWS), familial
evidence suggests that pyrin functions in the context of large protein 534
470 cold urticaria (FCU) which is also known as familial cold-associated syn-
complexes. In such complexes, the inclusion of molecules with reduced 535
E
471 drome (FCAS), and neonatal-onset multisystemic inflammatory disease

function could potentially compromise complex function. 536
472 (NOMID) syndrome [99]. Finally, an autoinflammatory disorder associ-
473 ated with deficiency of IL-1Ra (DIRA) has been described [100]. All of
R
5.1.2. Tumour necrosis factor receptor-associated periodic syndrome 537

474 these auto-inflammatory disorders have a common clinical feature in
(TRAPS) 538
475 intermittent episodes of heightened systemic or local inflammation, as
TRAPS is a rare autosomal dominant disease. It was initially called 539
R
476 well as a common mechanism in aberrant innate immune system

Familial Hibernian Fever because the first recognised cases were from 540
477 function. Here, we shall describe FMF, TRAPS, NOMID and DIRA in
Hibernia, the name given to Ireland by the Romans [116]. Since 541
478 more detail, detailing how cytokine and chemokines contribute to the
O
then, cases have been described from Europe and Asia, including 542
479 symptoms of the diseases.
Armenians, Sephardic Jews, Arabic and Japanese [117]. It is one of the 543
most commonly arising hereditary periodic fevers and is the second 544
C
480 5.1.1. Familial Mediterranean fever (FMF) most common globally after FMF, with an age of onset of 3 years 545
481 FMF is characterised by recurrent attacks of fever and serositis with [118]. The disease is characterised by recurrent attacks of fever, abdom- 546
N
482 significant acute-phase inflammation [101]. The age of FMF onset is typ- inal pain, migratory myalgia, rash and periorbital oedema. In addition, 547
483 ically before five years, with over 90% of patients becoming symptomat- some patients develop secondary systemic amyloidosis, which is poten- 548
484 ic within the first two decades of life. The diagnosis of FMF is made tially fatal [118,119]. The attacks usually continue for several days to 549
U
485 based on the clinical symptoms during a bout of the illness. Typically, weeks but much shorter attacks have also been observed. 550
486 an attack has a sudden onset with high fever and lasts from some In 1998, two groups of investigators independently mapped the sus- 551
487 hours to 3–4 days; the frequency varies from once per week to once ceptibility loci for patients with familial Hibernian Fever and autosomal 552
488 every few years. The signs of acute serosal inflammation include perito- dominant familial periodic fever to the same distal region of chromo- 553
489 nitis (90%), pleuritis (45%), scrotitis (5%) and pericarditis (1%), with some 12p [120,121]. These data strongly suggested that the same 554
490 erysipelas-like skin lesions reported in 7–40% of patients. There is also locus was responsible for the phenotype expressed in both of these syn- 555
491 evidence of increased neutrophil infiltration in the affected tissues dromes. Review of existing genomic databases revealed several posi- 556
492 [102]. Typical laboratory findings during an attack include leukocytosis, tional candidate genes including CD4, LAG-3, CD27, C1R, C1S, and 557
493 an elevated erythrocyte sedimentation rate and increased acute phase tumour necrosis factor (TNF) receptor super family 1A (TNFRSF1A). Of 558
494 reactants (serum amyloid A, fibrinogen, C-reactive protein) [103–105]. these, TNFRSF1A was particularly attractive in light of the central role 559
495 Several studies have now shown that these components are also elevat- that its protein product, TNFR1, plays in inflammation. Consequently, 560
496 ed between attacks in FMF patients [106–108]. This indicates that a collaborative effort was undertaken to sequence TNFRSF1A among af- 561
497 though their overt attacks are self-limited in nature, FMF patients expe- fected and unaffected members from seven families with autosomal 562
498 rience subclinical inflammation when asymptomatic. dominantly inherited recurrent fever syndromes [122]. Sequence 563
564 analysis of the ten exons of TNFRSF1A identified six different missense cytokines. Together, these actions synergise to generate the increased 595
565 mutations in patients that were not present in controls; five of these inflammation observed in TRAPS. 596
566 mutations involved highly-conserved cysteine residues that were Since the discovery that TNFRSF1A gene mutations drive TRAPS pa- 597
567 present in all 40 symptomatic patients and in only two asymptomatic thology a major area of clinical focus has revolved around development 598
568 family members. Thus, the discovery of mutations in TNFRSF1A led to of anti-TNFα biologics. Etanercept (Enbrel®; manufactured by Pfizer 599
569 a consolidation of these diseases under the name TRAPS. Inc.), a chimeric fusion protein coupling soluble TNFR2 to the IgG1 con- 600
570 There are currently over 90 reported mutations in TNFRSF1A leading stant region, was the first anti-TNFα drug successfully used to treat 601
571 to TRAPS (INFEVERS TRAPS database http://fmf.igh.cnrs.fr/infevers). An TRAPS patients. Although relatively well tolerated, etanercept is howev- 602
572 early indication of functional mechanism linked to TRAPS pathophysiol- er ineffective in some patients [126] and in others becomes less effective 603
573 ogy came from the demonstration of defective receptor shedding from with repeat doses [127]. Infliximab (Remicade®, manufactured by 604
574 peripheral blood mononuclear cells isolated from patients possessing Janssen Biotech, Inc.), a chimeric anti-TNF monoclonal antibody, has 605
575 the C52F mutation in TNFR1 [122]. The situation is not straightforward also been administered to patients with TRAPS. However not only are 606
576 however, as multiple modes of TNFR1 trafficking dysfunction have there a number of potentially dangerous side effects to the drug, but cer- 607
577 since been reported [123]. However all are thought to alter activity of tain TRAPS mutations are actually associated with an acute inflammato- 608
F
578 the transcription factor NF-κB (Fig. 7), although distinct differences in ry response to infliximab, most likely due to constitutive signalling 609
579 NF-κB subunit activity profiles have been reported for some of these resulting from failure to remove infliximab-bound TNF/TNFRI from the 610
O
580 mutations. Specifically, in addition to p65/p50 heterodimer subunit ac- cell surface of cells of peripheral blood mononuclear cells where the 611
581 tivity, the R92Q mutation has been shown to lead to increased activity of TRAPS-associated mutation in TNFRSF1A is associated with a shedding 612
582 the NF-κB p50/p50 subunit homodimer [124]. Thus, the low disease defect [128]. 613
O
583 penetrance associated with this mutation could be due to a repressive TNFRSF1A mutation and downstream NF-κB activation result in in- 614
584 function of the p50/p50 homodimer. More recent work has shown creased levels of pro-inflammatory cytokines, including IL-1β, in both 615
585 that whilst p65 subunit activity is elevated by different TRAPS muta- serum and peripheral mononuclear cells of TRAPS patients [125,129]. 616
R
586 tions, c-Rel subunit activity is also elevated in peripheral blood mono- The recombinant human IL-1R1 antagonist, anakinra (Kineret®; 617
587 nuclear cells isolated from TRAPS patients with F60L and Δ42 manufactured by Swedish Orphan Biovitrum), has therefore been ad- 618
P
588 mutations [125]. Interestingly, while high p65 activity was associated ministered to TRAPS patients in an attempt to reduce inflammatory ep- 619
589 with elevated IL-8 secretion, high c-Rel activity increased IL-1β and IL- isodes. Initial findings indicate sustained beneficial action of this drug in 620
590 12 secretion. Different TRAPS mutations therefore generate distinct the treatment of TRAPS [130,131]. However, as with all anti-cytokine
D 621
591 NF-κB family subunit activities and this, in turn, results in the generation therapies care will need to be taken to investigate potentially damaging 622
592 of unique cytokine secretory profiles [125]. Thus, it would appear that effects of repeated administration. Indeed, it should be noted that low 623
593 the NF-κB p65 and c-Rel subunits function as independent pro- concentrations of IL-1β actually have a positive physiological effect on 624
E
594 inflammatory mediators in TRAPS, promoting the secretion of different proliferation of certain cell types, such as pancreatic β-cells, and that 625
T
A) Soluble
TNFα
B) Soluble
TNFα
C
E
TNFR1 TNFR1
wild-type R92Q
R
D D
D D
R
Complex I TRADD TRAF2 Complex I TRAF2

TRADD
RIP RIP
O
IKK
IKK
C
NEMO
Ub
NEMO Ub
N
Iκ Bα
Iκ Bα P P
P P Iκ Bα
U
Iκ Bα NF-κB p50 p50
NF-κB p65 p50
Gene Transcription
p50 p50
Gene Transcription
Inflammation Gene Transcription
p65 p50 and cell
survival
p50 Bcl-3
Fig. 7. Signalling to NF-κB activation from wild-type and mutant TNFR1. A) The pathway induced by wild-type TNFR1. B) The R92Q variant of TNFR1 induces activation of the p50/p50
homodimer, leading to repression of NF-kB-dependent gene expression. However p50 can form dimers with Bcl-3, which has a transactivation domain and thus can induce inflammatory
gene expression. Further partners can be recruited to the p50/Bcl-3 heterodimer, leading to the activation of numerous off-target genes.
626 pharmacological IL-1β deficiency leads to a reduction in cell prolifera- 1Ra, patients cannot control systemic inflammation caused by IL-1 sig- 690
627 tion and secretory function in these cells [132]. nalling [149]. Although mutations that cause DIRA are rare there are 691
nonetheless hotspots, with for instance 2.5% of the population of north- 692
628 5.1.3. Neonatal onset multisystem inflammatory disease (NOMID) west Puerto Rico being carriers [149]. Since DIRA is recessively 693
629 NOMID, also known as chronic infantile neurologic cutaneous artic- inherited, these data suggest that it may be present in about 1 in 6,300 694
630 ular (CINCA) syndrome, belongs to the cryopyrin-associated periodic births in this population. Mutations may also be more common in indi- 695
631 syndromes (CAPS). It affects numerous organs and body systems, in- viduals of Dutch descent. Given the basis of the disease in the absence of 696
632 cluding the skin, joints, eyes, and the CNS. For most children, the first IL-1Ra, it is not surprising that the recombinant IL-1Ra drug, anakinra, 697
633 sign of the disease is a rash that develops within the first six weeks of has been successful in treating the symptoms of DIRA. 698
634 life. Other problems can follow, including fever, meningitis, joint dam-
635 age, vision and hearing loss and mental retardation. The disease is the 5.2. Pro-inflammatory disorders 699
636 most severe CAPS disorder and frequently results in death in affected
637 children [133]. While the mechanism of NOMID is not completely un- 5.2.1. Inflammatory bowel diseases 700
638 derstood, research has revealed mutations in the NLRP3 (NLR family Inflammatory bowel diseases (IBD), including Crohn's disease (CD) 701
F
639 pyrin domain 3) gene (formerly known as CIAS1) in approximately and ulcerative colitis (UC), are characterised by chronic, self-destructive 702
640 60% of patients with the disease [134]. NLRP3 encodes cryopyrin, inflammation of the gastrointestinal tract [150]. In both UC and CD, 703
O
641 which combines with caspase-1 and ASC to form the inflammasome leukocyte infiltration into the intestine is fundamental to disease devel- 704
642 complex that cleaves pro-IL-1β to generate its mature form [135]. opment and progression, with chemokines and their receptors mediat- 705
643 These mutations typically result in excessive secretion of IL-1β [136, ing tissue-specific and cell type-selective trafficking of leukocytes [151]. 706
O
644 137]. Thus, patients with NOMID usually respond well to anakinra, Several chemokine pathways have been identified as being central to 707
645 resulting in marked improvement both in symptoms and the underly- the physiopathology of IBD, including the CCL20–CCR6 and CCL25– 708
R
646 ing inflammation. Likewise, other patients with CAPS disorders show CCR9 ligand/receptor combinations [152]. Recently, the selective re- 709
647 improved symptoms with anakinra [138–140]. moval of leukocytes expressing CCR9 by using CCL25 as bait resulted 710
648 The short half-life of anakinra necessitates daily injections and injec- in substantial improvement in clinical symptoms in IBD [153]. In addi- 711
P
649 tion site reactions are commonly observed [138–141]. Newer therapeu- tion, the homeostatic and inflammatory roles of the CX3CL1–CX3CR1 712
650 tics with improved pharmacokinetics and tolerance have been and CXCL10–CXCR3 pathways offer promising molecular targets for 713
651 developed. Rilonacept (Arcalyst™; Regeneron Pharmaceuticals) is an therapeutic intervention [152]. There is also evidence of cytokine acti-
D 714
652 artificial molecule that contains the ligand-binding portions of both IL- vation in the mucosal immune system [154,155], with increased levels 715
653 1R1 and IL-1AcP fused to a dimeric molecule containing the Fc segment of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Based on 716
654 of hIgG1 (human immunoglobulin G1) [142]. It thus acts by binding to these observations a rationale for anti-TNFα and other anti-cytokine 717
E
655 IL-1 with an affinity at least 100-fold higher than that of the native IL- therapy was defined, and clinical studies have led to some promising re- 718
656 1R complex, thereby preventing IL-1 binding to cell surface receptors sults [156–159]. A number of large studies have also shown the efficacy 719
T
657 [142]. In contrast to anakinra, rilonacept has a half-life of approximately of TNFR and anti-TNFα therapy in RA and Crohn's disease [160–163]. 720
658 seven days and thus is administered once weekly [143]. Rilonacept has
C
659 been approved by the FDA for the treatment of CAPS and it has proven 5.2.2. Allergic diseases and asthma 721
660 very effective and safe in a small open-label pilot study patients with Aberrant regulation of chemokine expression has been implicated in 722
661 FCAS and MWS [144,145]. In addition to improving symptoms of the a number of diseases including allergy and asthma (Table 5). Inflamma- 723
E
662 disease, rilonacept also reduced serum levels of serum amyloid A tion is also a key factor in asthma, in which the chemokine CCL11 724
663 (SAA) [143,145]. The latter is of great importance given that high (eotaxin) and its receptor, CCR3, contribute to the recruitment of eosin- 725
R
664 serum levels of SAA are directly related to the risk of developing second- ophils to the lung [164]. Increased chemokine levels have been ob- 726
665 ary amyloidosis [108], the main cause of renal insufficiency in these pa- served in asthmatic patient bronchoalveolar lavage and biopsy 727
666 tients. Injection site reactions and upper respiratory tract infections samples [165,166], including CCL2, CCL3, CCL5, CCL7, CCL11, CCL13, 728
R
667 were the two most commonly observed adverse events in patients CCL24, /IL-8, and CXCL10. In addition, murine models of asthma have 729
668 treated with rilonacept [143]. implicated chemokine induction of AHR and cellular emigration 730
O
669 A third IL-1 blocker, the monoclonal human anti-IL-1β canakinumab through CCL2, CCL5, CCL11, CXCL10, and CXCL12 in airway inflamma- 731
670 (Ilaris®, manufactured by Novartis Pharmaceuticals), was used in pa- tion [167,168]. Furthermore, the chemokine CCL11 (eotaxin) and its re- 732
671 tients with CAPS in one small study [146] and in a randomised ceptor, CCR3, contribute to the recruitment of eosinophils to the lung 733
C
672 placebo-control clinical trial [147]. Canakinumab was administered sub- [164]. 734
673 cutaneously once every eight weeks and induced a remarkable clinical The C–C chemokine family has been extensively studied in allergic 735
N
674 response with normalisation of SAA and C-reactive protein levels diseases because of their ability to recruit eosinophils, T cells, and mono- 736
675 [147]. During the treatment period, only two adverse events were ob- cytes to regions of inflammation. CCL5 and CCL11 are the most impor- 737
676 served – a case of urosepsis and an episode of vertigo [147]. tant eosinophil chemoattractants in allergic inflammation [169]. Aside 738
U
from production by eosinophils, macrophages, mast cells, and T cells, 739

677 5.1.4. Deficiency of interleukin-1 receptor antagonist (DIRA) CCL5 and CCL11 are produced by structural cells of the airway, including 740
678 DIRA was recently reported as a new autosomal recessive airway smooth muscle and fibroblasts. In addition to lymphoid tissue, 741
679 autoinflammatory disease caused by mutations of IL1RN, the gene nasal epithelial cells express CCL17 (TARC), and expression of this che- 742
680 encoding the IL-1 receptor antagonist, with prominent involvement of mokine and its receptor, CCR4, was higher in patients with allergic rhi- 743
681 skin and bone [100]. Children with this disorder display a constellation nitis compared with that seen in nonallergic control subjects. Both IL-4 744
682 of serious and potentially fatal symptoms, including swelling of bone and IL-13 promote CCL17 expression, leading to a Th2 response [170]. 745
683 tissue, bone pain and deformity, inflammation of the periosteum and a This is relevant in allergic bronchopulmonary aspergillosis (ABPA), in 746
684 rash that can span from small individual pustules to extensive which increased serum levels of CCL17 predict ABPA exacerbations bet- 747
685 pustulosis that covers most of the patient's body. Most of the children ter than IgE levels [171]. CCL17 levels might also serve as a marker of 748
686 begin to have symptoms from birth to 2 weeks of age. Although it has ABPA in patients with cystic fibrosis [172]. 749
687 only recently been described, there is evidence from previous case stud- IL8 is derived primarily from mononuclear phagocytes, endothelial 750
688 ies that could be describing DIRA, with severe infantile chronic multifo- and epithelial cells, but is also produced by T cells, eosinophils, neutro- 751
689 cal osteomyelitis and pustulosis [148]. In the absence of functional IL- phils, fibroblasts, keratinocytes, hepatocytes, and chondrocytes. IL8 752
753 synthesis can be induced by LPS, IL-1, TNFα, or viral infection [173,174]. combined effects of APCs and γδ T cells are thought to lead to neutrophil 818
754 On a molar basis, IL8 is one of the most potent chemoattractants for neu- hyperactivity [182]. Neutrophils are hyperactive in BD, with increased 819
755 trophils in addition to stimulating the neutrophil respiratory burst and chemotaxis, phagocytosis, superoxide production and myeloperoxidase 820
756 adherence to endothelial cells through CXCR1 [174]. However, a num- expression, as well as producing several cytokines, including IL-12 [188, 821
757 ber of additional chemokines also contribute to allergic inflammation, 189]. Given the aforementioned responsiveness of the γδ T cells in BD, 822
758 with different Th cell responses and temporal contributions reflecting this additional secretion of IL-12 by neutrophils is likely to exacerbate 823
759 a complex series of interactions. For example in asthmatic lungs the symptoms. 824
760 CXCL10 and CXCL13 are induced at different times after allergen expo-
761 sure, with CXCL10 produced in early phases, and CXCL13 only induced 5.2.4. Rheumatoid arthritis (RA) 825
762 after secondary and subsequent exposures. [175]. This likely reflects Rheumatoid arthritis is an autoimmune disease characterised by the 826
763 the cellular sources of these cytokines, with airway epithelial cells pro- presence of autoantibodies (rheumatoid factors) and chronic inflamma- 827
764 ducing CXCL10, whereas CXCL13 is produced by Th17, but not Th1 or tion that leads to tissue destruction [92]. A role for dysregulation of cy- 828
765 Th2, cells. It is thus tempting to speculate that Th17 cells might play a tokines in the synovial tissues was identified early on as a potential 829
766 role in asthma in later exposures after the allergic phenotype has al- factor in RA pathogenesis [190]. This led to the discovery that anti- 830
F
767 ready been established. T cell subsets that might have regulatory activ- TNFα antibodies inhibited the production of IL-1 in these tissues and 831
768 ity are being identified, and chemokines and their receptors appear to the suggestion that TNFα induced IL-1 production by synovial cells 832
O
769 have important roles in mediating activity and migration of these [191]. At around the same time elevation in TNFα was linked to the 833
770 cells. Among CD4+CD25+Foxp3+ nTreg cells, there appears to be at pathogenesis of polyarthritis in mice [192]. Importantly, this study 834
771 least 2 subgroups that can be distinguished based on CCR6 expression. also demonstrated that administration of an anti-TNFα monoclonal an- 835
O
772 Those that are high in CCR6 seem to have regulatory activity, whereas tibody prevented development of the disease in these animals. Subse- 836
773 those low in CCR6 secrete Th2 cytokines on stimulation with bacterial quently the expression of both TNFR1 and TNFR2 was found to be 837
774 superantigen [176]. Another group has demonstrated low levels of upregulated in synovial tissues of patients with RA [193]. Combined 838
R
775 XCR1 on the surface of CD4+CD25hiCD127low Treg cells isolated from with the prior observations, this evidence established TNFα as the key 839
776 allergic asthmatic subjects compared with those from healthy control pathogenic cytokine in RA. 840
P
777 subject [177]. Although in a relatively early stage, this emerging field Chimeric anti-TNFα monoclonal antibodies were developed for clin- 841
778 of chemokine response and expression by Treg cells will hopefully clar- ical trials in humans and found to be highly successful in improving 842
779 ify many of the questions about how these cells work. markers of RA in patients [194]. The chimeric monoclonal antibody,
D 843
infliximab, was subsequently approved for use in the treatment of RA 844
780 5.2.3. Behçet's disease [92]. In addition, other monoclonal anti-TNFα therapeutics have been 845
781 Behçet's disease (BD) is a multi-centre inflammatory disease, with developed with various modifications to improve efficacy or safety, 846
E
782 symptoms including oral and genital canker sores or ulcers and ocular such as the recombinant, fully-human antibody adalimumab [92]. In- 847
783 inflammation. In some patients, the disease also results in arthritis, tensive research on the role played by cytokines in RA has thus lead to 848
T
784 skin problems, and inflammation of the digestive tract, brain, and spinal advances in therapeutics, particularly the development of novel anti- 849
785 cord [178]. Behçet's disease is common in the Middle East, Asia, and TNFα therapies. 850
C
786 Japan, although it is rare in the United States. In Middle Eastern and The BeSt trial revealed that several patients with early RA receiving 851
787 Asian countries, the disorder affects more men than women, while in infliximab (TNFα blockade) with methotrexate were able to stop 852
788 the United States the opposite is true. Behçet's disease tends to develop treatment (if they reached a low disease activity state without 853
E
789 in patients in their twenties or thirties. Whilst the precise cause of subsequent disease flare) [195]. Remarkably, a proportion of patients 854
790 Behçet's disease is currently unknown, the majority of symptoms result remained in clinical remission for up to 4 years, with a small number 855
R
791 from inflammation of blood vessels. Serum levels of several cytokines (14%) being drug-free (i.e., not being treated with disease-modifying 856
792 are elevated, including IL-1, IL-4, IL-6, IL-8, IL-10, IL-13, IL-18 and anti-rheumatic drugs (DMARDs)) [195]. Currently, the outcome of 857
793 TNFα [179,180], while IL-15 levels in the cerebral spinal fluid (CSF) such trials is leading clinicians to question whether treatment with 858
R
794 were higher in patients with BD of patients than in patients in remission anti-TNFα therapeutics can eventually lead to remission and the ability 859
795 or healthy controls [181]. Corticosteroids and immunosuppressive to discontinue the use of such agents in patients who have achieved re- 860
O
796 drugs are commonly used to treat the disease. mission [196]. For some patients on adlimubab or infliximab with meth- 861
797 It has been demonstrated that there is a polarisation of the T cell re- otrexate who have been in remission for an extended period of time, 862
798 sponse in BD towards the production of type I cytokines (a Th1 re- discontinuation of the treatment could be feasible [196]. 863
C
799 sponse) [182,183]. Previous work showed a preponderance of the While TNFα clearly has a pivotal role in RA, several other cytokines 864
800 CXCR3+ CD3+ subset of Th1 cells in BD [183]. The γδ T cells have a are present in the synovial tissue and could also contribute to pathogen- 865
N
801 non-redundant role in immune responses, particularly to bacterial in- esis. Among these is IL-6, which signals via a JAK-STAT pathway. Recent- 866
802 fections. They also make potent anti-tumour responses and have been ly, an inhibitor of JAK signalling has been developed and this is now 867
803 implicated in various autoimmune diseases. Patients with BD have in- approved for use in the treatment of moderate to severe RA. The small 868
U
804 creased numbers of γδ T cells in circulation and in mucosal lesions molecule JAK inhibitor, tofacitinib (Xeljanz;® manufactured by Pfizer 869
805 [184]. In one study there was an elevated number of the Vγ9Vδ2 subset Inc.), is to be used initially as a second-line therapy for patients who 870
806 of γδ T cells in the intraocular fluid of BD patients with uveitis [185]. The fail to respond to methotrexate or anti-TNFα biologicals [197]. Thus 871
807 γδ T cells in BD have an activated phenotype, expressing markers such the early success of TNFα inhibition is serving as a model for developing 872
808 as CD25, CD29 and CD69, and producing pro-inflammatory cytokines, other treatments of RA that target cytokine signalling pathway compo- 873
809 such as IFN-γ, TNFα and IL-8 [182]. Further, the γδ T cells from BD pa- nents to limit inflammation. 874
810 tients proliferate in response to mycobacterial HSP-derived peptides Whilst blockade of TNFα is often beneficial in the short-term, it is not 875
811 and in response to products from microorganisms in oral ulcers [184, curative, and its effects are often only partial and non-responsiveness is 876
812 186]. Importantly, γδ T cells also proliferate in the presence of IL-12 also common. Moreover, loss of effect has been observed. Despite 877
813 and it has been demonstrated that serum levels of IL-12 are increased advances in the treatment of RA, particularly the anti-cytokine thera- 878
814 in BD [187]. In addition to T cells, it is likely that antigen-presenting peutics, it is still a formidable clinical problem with the risk of progres- 879
815 cells (APCs) contribute to BD by the cytokines they secrete, including sive articular damage (radiographic progression), functional decline 880
816 IL-12 and IL-18; the former contributes to T cell activation, while the and comorbidities remain for many patients. Crucially, there is as yet lit- 881
817 latter has been shown to stimulate neutrophils [182]. Indeed, the tle evidence that we can re-establish immunologic tolerance and hence 882
883 aim for drug-free remission on a regular basis. Drug responses and tox- likely via the release of potent pro-inflammatory molecules [213] and 946
884 icities remain idiosyncratic, with few reliable biomarkers for prognostic other immunomodulatory molecules which lead to the recruitment of 947
885 or therapeutic purposes having been identified thus far. One therapeutic monocytes and lymphocytes through the blood-brain barrier (BBB) 948
886 strategy would be to evaluate and target specific cytokines present at [214,215]. This leads to activation of additional microglia and also pro- 949
887 particular stages of the disease. Alternatively, the combination of anti- motes their proliferation, thereby amplifying the release of inflammato- 950
888 TNFα therapeutics with other drugs, such as the new JAK inhibitor ry factors [216]. 951
889 [197], could result in improved clinical outcomes. Soluble Aβ oligomers are thought to activate microglia via stimula- 952
tion of innate immune receptors [212], thus triggering the above- 953
890 5.3. Neurological disorders involving inflammation mentioned inflammatory process. Amyloid plaques are also thought to 954
attract and activate microglia, leading to clustering of microglia around 955
891 Inflammation is a process that is implicated in the onset of various Aβ deposit sites in the brain [217]. Microglia also express scavenger re- 956
892 neurodegenerative diseases. Over the last decade increasing knowledge ceptors that mediate adhesion of the microglia to Aβ fibril-coated sur- 957
893 has emerged on the role of cytokines in brain physiology. As for other faces, thus leading to ROS secretion and cell immobilisation [218]; the 958
894 organs, excessive cytokine expression in the brain is harmful and has secretion of ROS is particularly associated with neuronal damage since 959
F
895 been associated with neurological disorders, including both Alzheimer's it can cause lipid and protein cross-linking and consequent loss of 960
896 disease (AD) and Parkinson's disease (PD). As will be discussed below, function. Microglia activated by Aβ secrete elevated levels of pro- 961
O
897 these complex neurodegenerative disorders are associated with compli- inflammatory cytokines and chemokines [213,219], the latter enhanc- 962
898 cated, multifactorial changes in inflammatory molecules. ing the ability of peripheral monocytes to pass through the BBB [220]. 963
Microglia exposed to Aβ can also be activated through receptors for ad- 964
O
899 5.3.1. Alzheimer's disease vanced glycation end products (RAGE) and macrophage colony- 965
900 The molecular and cellular mechanisms responsible for the aetiology stimulating factor (M-CSF) [221]. M-CSF induces further microglial che- 966
R
901 and pathogenesis of AD have been widely studied and several hypothe- motaxis towards Aβ, and also increased macrophage scavenger receptor 967
902 ses advanced. While the hypotheses differ in the initiating trigger for the expression. Interestingly, removal of M-CSF from cultures resulted in 968
903 disease, inflammation within the brain is thought to play a pivotal role. apoptosis of microglia [222], whilst treatment of microglia with anti- 969
P
904 Studies suggest that peripheral infection or inflammation could also af- RAGE F(ab′)2 resulted in decreased secretion of M-CSF and reduced 970
905 fect the inflammatory state of the central nervous system (CNS). This in- chemotaxis towards Aβ [221]. This would seem to suggest that thera- 971
906 cludes chronic periodontitis, which has been associated with several peutic strategies that employ similar rationales might offer patients
D 972
907 systemic diseases such as AD [198]. Other hypotheses include the out- with AD an improved prognosis. 973
908 come of viral infection of the CNS triggering either a chronic inflamma- The presence of microglia around Aβ plaques is not necessarily det- 974
909 tory state or even inducing autoimmune dysfunction within the brain. rimental however, as M-CSF induction of microglia to the parenchyma 975
E
910 Chronic infection with herpes simplex virus type 1 (HSV1) and its reac- of Swedish β-amyloid precursor protein (APPSwe)/PS1 transgenic 976
911 tivation from latency are associated with AD pathology [199,200]. In ad- mice has been shown to decrease the number of Aβ deposits and pre- 977
T
912 dition, activation of TLRs on microglia by bacterial infections in the CNS vent cognitive loss compared to vehicle controls [223]. These findings 978
913 can contribute to neuronal cell death and AD symptoms [201]. Thus the support the view that M-CSF stimulates and attracts bone marrow- 979
C
914 initiating trigger could be either localised infection in, or the impact of derived microglia into the CNS, and induces neuroprotective functions 980
915 peripheral inflammation on, the CNS. in microglia leading to Aβ clearance. However microglia are not the 981
916 The pathology of AD is characterised by proteinaceous lesions within only cells in the CNS to internalise Aβ, and the uptake of these peptides 982
E
917 the brain as well as by neuronal loss. Pathological lesions such as amy- by astrocytes and neurons also likely contributes to AD pathology. As- 983
918 loid plaques containing the cleaved Aβ protein and neurofibrillary tan- trocytes contribute to Aβ clearance and degradation, as well as provid- 984
R
919 gles containing tau protein are frequently observed in the brains of AD ing trophic support to neurons and forming a protective barrier 985
920 patients [202]. Emerging evidence suggests that inflammatory re- between Aβ deposits and neurons [224,225]. Astrocytes have been 986
921 sponses contribute to the progression of AD, accelerating the course of found to cluster around Aβ deposits and these deposits are thought to 987
R
922 the disease. Under the influence of IL-1 originating from activated activate inflammatory signalling in astrocytes [212]. Likewise, in a 988
923 microglia, astrocytes in neurite plaques were found to over-express mouse model of AD, astrocytes were found to degrade Aβ (1–42) pep- 989
O
924 the neurotrophic calcium binding protein, S100B [203]. Over- tides in vitro and in situ, thereby clearing the Aβ deposits in what is 990
925 expression of S100B has been found to accelerate AD-like pathology in hypothesised to be a protective housekeeping function of these cells 991
926 a transgenic mouse model [204]. Additionally, the expression of α1- [224]. However, their tendency to release pro-inflammatory molecules 992
C
927 antichymotrypsin (ACT), a protein associated with amyloid plaques in is thought to stimulate and even accelerate the progression of AD. Astro- 993
928 AD [205], was found to increase in response to the treatment of astrocytes activated by Aβ produce chemokines, cytokines, and ROS that may 994
N
929 cytes with IL-1 and IL-6 [206]. AD brains were also found to have high result in neuronal damage [226,227]. Importantly, it has been found that 995
930 levels of nitrous oxide synthase (NOS)-positive astrocytes compared neurons can also take up Aβ peptides and the internalisation of Aβ by 996
931 to controls [207], suggesting increased production of NO in the AD neurons is considered to be one of the earliest signs of AD [228]. This 997
U
932 brain. In support of this, Aβ peptides induced astrocytes to produce IL- finding is consistent with the results of previous studies which have 998
933 1β, NOS mRNA and NO [208]. More recently, a feed-forward mechanism shown that the Aβ obtained from phagocytosed neurons accumulates 999
934 was proposed, whereby Aβ activation of astrocytes results in the pro- within astrocytes and that amyloid plaques form when these Aβ- 1000
935 duction of APP and the BACE enzyme responsible for Aβ cleavage, gen- burdened astrocytes die [229]. Chemokines released by astrocytes 1001
936 erating more peptides that contribute to plaque formation [209]. also attract microglia, thus further adding to the complexity of AD 1002
937 Regardless of the cause, inflammation in the CNS involves the activa- pathogenesis. 1003
938 tion of microglia and astrocytes, resulting in the release of inflammatory Finally, neurons themselves appear to contribute to the production 1004
939 mediators such as cytokines, chemokines, neurotransmitters and reac- of neuroinflammatory products in AD, although they were traditionally 1005
940 tive oxygen species (ROS) [210]. Microglia are particularly important believed to be passive bystanders in neuroinflammation. Neurons pro- 1006
941 in the CNS immune response and are generally thought to be neuropro- duce several chemokines and cytokines including IL-1 [230,231], IL-6 1007
942 tective, with resting microglia becoming activated in the presence of [232] and TNFα [228]. Neuronal chemokines in particular act as mes- 1008
943 pathogens, damaged cells and cell debris, and functioning to clear per- sengers between neurons and glial cells [233,234]; the secretion of 1009
944 ceived danger signals to protect neurons [211]. However there is also CD22 by neurons inhibits pro-inflammatory cytokine production in mi- 1010
945 evidence that microglia can have neurotoxic effects in the brain [212], croglia [235]. In addition, neurons are able to serve as a source of 1011
1012 complement proteins [236–238], pentraxins, C-reactive protein, amy- transactivating subunit, NF-κB RelA (p65), has been reported to be 70- 1077
1013 loid P [239], cyclooxygenase (COX)-2-derived prostanoids [220, fold greater in the SN of PD patients compared age-matched healthy 1078
1014 240–242] and inducible NOS [243]. Thus, the secretion of pro- controls [268]. A relationship between enhanced nuclear translocation 1079
1015 inflammatory molecules by neurons could serve to enhance the inflam- of NF-κB and oxidative stress in DA neurons of PD patients is supported 1080
1016 mation in the brain due to the response of glial cells to the Aβ- by in vivo studies in which 6-OHDA-induced oxidative stress in rat DA 1081
1017 containing plaques, thereby contributing to the pathogenesis of AD. neurons was mediated by an NF-κB-dependent p53-signalling pathway 1082
[269]. Indeed, therapeutic agents for PD that are designed to inhibit NF- 1083
1018 5.3.2. Parkinson's disease κB activation have been described [256]. The NF-κB essential modulator 1084
1019 PD is the most common neurodegenerative movement disorder (NEMO)-binding domain (NBD) peptides, which inhibit the activation 1085
1020 [244], with symptoms including resting tremor, slowed movement, of NF-κB signalling, have been shown to attenuate the glial response 1086
1021 postural instability and muscle rigidity, as well as non-motor symptoms and MPTP-induced nigral degeneration [270]. Similarly, the synthetic 1087
1022 [245,246]. It is an age-dependent disorder characterised by the progres- triterpenoid CDDO-Me, a potent activator of the Nrf2 anti-oxidant path- 1088
1023 sive degeneration of dopaminergic (DA) neurons in the substantia nigra way and an inhibitor of NF-κB, attenuates the production of TNFα and 1089
1024 (SN). In addition, inclusions called Lewy bodies (LBs), which are com- other glial-derived inflammatory mediators, thereby reducing the neu- 1090
F
1025 posed of α-synuclein and ubiquitinated proteins, are found within the rotoxicity of activated microglial cultures on DA neuron-like cells [271]. 1091
1026 remaining SN neurons [247]. There is debate about whether LBs directly Further, the brain-permeable methyl amide derivative (CDDO-MA) was 1092
O
1027 cause neuronal death or perhaps sequester smaller neurotoxic protein recently shown to afford neuroprotection in vivo against MPTP and 6- 1093
1028 aggregates to preserve neuronal viability [248–250]. The motor symp- OHDA-induced nigral degeneration in mice and rats [272]. Thus, there 1094
1029 toms can be treated with DA therapeutics; however, the effectiveness is evidence from in vivo pharmacological studies showing that the inhibi- 1095
O
1030 of these agents diminishes as the severity of the clinical symptoms in- tion of oxidant-mediated apoptogenic transduction pathways and NF-κB 1096
1031 creases due to progression of the underlying neurodegeneration [251]. activation protects against DA neuronal loss, providing support for a link 1097
1032 The recent identification of mutations in several genes linked to rare between oxidative stress and inflammation in PD pathogenesis [273]. 1098
R
1033 inherited forms of PD has led to speculation that these mutations Numerous therapeutic agents used to treat inflammation or for im- 1099
1034 promote inclusion formation, ubiquitin–proteosome system (UPS) dys- munosuppression have been found to ameliorate markers of PD. The 1100
P
1035 function and nigral cell loss, although the precise molecular mecha- immunosuppresants, cyclosporine A and FK-506 (tacrolimus), the 1101
1036 nisms are unclear and the pathology in humans and animal models non-immunosuppressant FK-506 derivatives (immunophilin ligands 1102
1037 bearing these mutations is highly variable [252,253]. Nevertheless, re- including pentoxifylline), as well as the non-selective COX-2 inhibitor
D 1103
1038 cent studies of transgenic animals with mutations linked to Parkinson- sodium salicylate, have all shown neuroprotective activity in either 1104
1039 ism, as well as neurotoxin- and virus-based animal models of PD, have MPTP-induced nigral injury or the 6-OHDA rat model of PD 1105
1040 provided valuable insight into potential pathogenic mechanisms involv- [274–276]. Despite this, clinical trials of immunophilin ligands in PD 1106
E
1041 ing neuroinflammation. Human clinical imaging, post-mortem exami- patients have had limited success [277], possibly due to the advanced 1107
1042 nations and epidemiological studies have recently highlighted the role nature of the disease in the patient cohort. Similarly, the glucocorticoid 1108
T
1043 of neuroinflammation in PD and raise the interesting possibility that dexamethasone was protective against both MPTP and intranigral LPS- 1109
1044 chronic inflammation may lead to symptoms of PD [254]. There has re- induced cell death [278,279]. The semi-synthetic second generation 1110
C
1045 cently been significant interest in developing novel anti-inflammatory tetracycline antibiotic derivative minocycline, which has anti- 1111
1046 agents that may help prevent or ameliorate CNS inflammation [255]. inflammatory properties and readily crosses the BBB, has been investi- 1112
1047 In this section, we will mention a few targets the modulation of which gated in rodent and non-human primate models of PD with mixed out- 1113
E
1048 has yielded promising results which may be translatable to the clinic comes. In some studies it was shown to be neuroprotective against 1114
1049 in the future. MPTP-, LPS- and 6-OHDA-induced nigral DA neuron loss [280–283], 1115
R
1050 The presence of activated microglial cells and elevated levels of while in others it exacerbated the effects of MPTP in rodents and non- 1116
1051 several pro-inflammatory cytokines are evident in post-mortem exam- human primates [284,285]. The reason for these discrepancies is unclear 1117
1052 inations of the SN [256,257]. An emerging area of pre-clinical investiga- but it could be due to differences in dosing and timing of the interven- 1118
R
1053 tion involves development of strategies to inhibit the glial reaction and tion regimen. Nevertheless, because minocycline is well-tolerated in 1119
1054 to target pro-inflammatory cytokines [258–260]. IL-1β levels have been humans, it was tested in a randomised, double-blind, futility clinical 1120
O
1055 reported to increase rapidly after administration of LPS into the SN in trial in patients with early PD. The recommendation at the completion 1121
1056 mice and neuroprotection can be achieved by administering an anti- of Phase II was for advancement to Phase III clinical trials to determine 1122
1057 IL-1β neutralising antibody [261,262]. In the case of TNFα, a rat model if minocycline could alter long-term progression of PD [286]. The results 1123
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1058 of PD found that inhibition of TNFα prevented DA neuronal cell of this study suggest that minocycline has a good safety profile and that 1124
1059 death. The use of a recombinant dominant negative TNFα inhibitor, it should be tested next in Phase III trials, although no such trial is on re- 1125
N
1060 XENP345, reduced neurotoxin- and endotoxin-induced DA neuronal cord. In part, this could be due to concerns over the worsening of symp- 1126
1061 death by approximately 50% [263]. In short, it is clear that targeting spe- toms observed with minocycline in the treatment of amylotrophic 1127
1062 cific inflammatory mediators has been a valuable approach to establish lateral sclerosis (ALS) [287]. Chemical modification of minocycline 1128
U
1063 the extent to which the various factors implicated in PD pathogenesis using structure–activity relationship analysis is being used to develop 1129
1064 contribute to loss of DA neurons in animal models. However, due to safer and more efficacious versions of the drug that can protect nigral 1130
1065 the complexity of the human disease and the interactions of inflamma- DA neurons at low doses [288]. 1131
1066 tory pathways, design of a successful intervention will very likely re- Other compounds with anti-inflammatory actions that have been 1132
1067 quire a multi-target approach during the earliest stages of PD. shown to rescue nigral DA neurons from a variety of neurotoxic insults 1133
1068 This complexity of PD pathogenesis is exemplified in the role of NF- such as LPS and MPTP include vasoactive intestinal peptide (VIP) [289, 1134
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1074 ly promotes their survival, whereas NF-κB mediates proliferation might be unsuitable for long-term use in humans. 1140
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BBAMCR-17280; No.

of pages: 20; 4C: 3, 4, 5, 6, 8, 10

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

1 Cytokines and chemokines: At the crossroads of cell signalling and

18 Chemotaxis ders, pro-inﬂammatory disorders, and neurological disorders involving inﬂammation. 29

37 ﬂammatory diseases. This advance of information has led researchers

39 ease, Alzheimer's disease, type 1 diabetes, type 2 diabetes and obesity

⁎ Corresponding author at: School of Science and Technology, Nottingham Trent

t1:4 Family Members

t2:3 Main sources Target cell Major function

t2:4 tion, BM cell proliferation

t2:11 IgG production

t2:14 IL-9 T cell T cell Growth and proliferation

t2:19 Monocytes Tumour cells Tumour cytotoxicity, cachexia

characterised by the presence of three to four conserved cysteine resi- 306

membrane-bound chemokine [59]. 321

t4:40 CXCL2 (GROβ, MGSAβ) CXCR2

CXCL4L1 (PF4V1) CRCR3

t4:46 CXCL7 (NAP-2) CXCR2

t4:49 CXCL10 (IP-10) CXCR3

CXCL13 (BLC, BCA-1) CXCR3, R5

CXCR1 or CXCR2 Neutrophil, T cell

418 matoid arthritis, lupus nephritis, psoriasis and systemic sclerosis

471 drome (FCAS), and neonatal-onset multisystemic inﬂammatory disease

5.1.2. Tumour necrosis factor receptor-associated periodic syndrome 537

476 well as a common mechanism in aberrant innate immune system

Complex I TRADD TRAF2 Complex I TRAF2

Iκ Bα NF-κB p50 p50

NF-κB p65 p50

from production by eosinophils, macrophages, mast cells, and T cells, 739

H. Kuhn, D. Stauffer, G. Rovelli, B. Martoglio, SPPL2a and SPPL2b promote 1255

2029 Neurochem. 81 (2002) 150–157. Neuroscience 110 (2002) 49–58. 2096

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