Journal of Pathology

J Pathol 2008; 214: 149–160

Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/path.2287

Invited Review

TNF-mediated inflammatory disease

JR Bradley*
NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK

*Correspondence to: Abstract

JR Bradley, NIHR Cambridge
Biomedical Research Centre, Box
118, Addenbrooke’s Hospital,
Cambridge CB2 2QQ, UK.
E-mail: jrb1000@cam.ac.uk
No conflicts of interest were
declared.
TNF was originally described as a circulating factor that can cause necrosis of tumours,
but has since been identified as a key regulator of the inflammatory response. This
review describes the known signalling pathways and cell biological effects of TNF, and
our understanding of the role of TNF in human disease. TNF interacts with two different
receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and
tissues and initiate both distinct and overlapping signal transduction pathways. These diverse
signalling cascades lead to a range of cellular responses, which include cell death, survival,
differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by
undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion,
transendothelial migration and vascular leak and promote thrombosis. The central role of
TNF in inflammation has been demonstrated by the ability of agents that block the action of
TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing
spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection
in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in
infectious diseases.
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
Keywords: tumour necrosis factor; signal transduction; inflammation; infection; arthritis;
therapy

Introduction
Tumour necrosis factor (TNF, also known as TNFα)
was identified in 1975 as an endotoxin-induced glyco-
protein, which caused haemorrhagic necrosis of sarco-
mas that had been transplanted into mice [1]. Human
tumour necrosis factor was cloned in 1985 [2], and
recombinant TNF was shown to induce the haem-
orrhagic necrosis of transplanted methylcholanthrene-
induced sarcomas in syngeneic mice. TNF has since
been implicated in a diverse range of inflammatory,
infectious and malignant conditions, and the impor-
tance of TNF in inflammation has been highlighted by
the efficacy of anti-TNF antibodies or administration
of soluble TNF receptors (TNFRs) in controlling dis-
ease activity in rheumatoid arthritis and other inflam-
matory conditions.
Production of TNF
TNF is produced predominantly by activated macro-
phages and T lymphocytes as a 26 kDa protein,
pro-TNF, which is expressed on the plasma mem-
brane, where it can be cleaved in the extracellular
domain by the matrix metalloproteinases, which result
in the release a soluble 17 kDA soluble form. Both
membrane-associated and soluble TNFs are active in
their trimeric forms, and the two forms of TNF may
have distinct biological activities. TNFα converting
enzyme (TACE, also known as ADAM-17) medi-
ates release of TNF from the cell surface [3], but is
involved in processing several cell-membrane asso-
ciated proteins, including TNF receptors, which are
released by its action to produce soluble froms that can
neutralize the actions of TNF [4]. TACE may there-
fore be either pro- or anti-inflammatory, depending on
whether it acts on an effector (eg macrophage) or tar-
get (eg endothelial) cell, releasing ligand or receptors,
respectively.
TNF is not usually detectable in healthy individ-
uals, but elevated serum and tissue levels are found
in inflammatory and infectious conditions [5,6] and
serum levels correlate with the severity of infections
[7,8]. Although cells of the monocyte/macrophage lin-
eage are the main source of TNF in inflammatory dis-
ease, a wide range of cells can produce TNF, including
mast cells, T and B lymphocytes, natural killer (NK)
cells, neutrophils, endothelial cells, smooth and car-
diac muscle cells, fibroblasts and osteoclasts.
TNF signal transduction
TNF signal transduction pathways are complex and
still not fully understood. Regulation of the transcrip-
tion factor NF-κB is a key component of TNF signal

Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
www.pathsoc.org.uk
150
Figure 1. Signalling pathways leading to the main cellular responses of TNF. Soluble TNF receptors or monoclonal anti-TNF
antibodies, which prevent TNF interacting with its receptors and activating these pathways, can be used to treat inflammatory
disease
transduction, but large-scale physical mapping in com-
bination with loss of function analysis using RNA
interference recently identified 221 molecular associa-
tions and 80 previously unknown interactors involved
in modulation of the TNF–NF-κB pathway alone [9].
All known responses to TNF are triggered by bind-
ing to one of two distinct receptors (Figure 1), des-
ignated TNFR1 (also known as TNFRSF1A, CD120a,
p55) and TNFR2 (also known as TNFRSF1B, CD120b,
p75), which are differentially regulated on various
cell types in normal and diseased tissue [10]. The
extracellular, ligand-binding domains of TNF recep-
tors contain cysteine-rich subdomains, characteristic
of members of the nerve growth factor/TNF recep-
tor gene family. In contrast, the intracellular domains
of the two receptors show no sequence homology and
are devoid of intrinsic enzyme activity, and activate
distinct signal transduction pathways by recruitment
of cytosolic proteins through specific protein–protein
interaction domains [11]. The ability of TNFR1 and
TNFR2 to interact with both identical and unrelated
molecules may explain their shared and diverse func-
tions. Based on cell culture work and studies with
receptor knockout mice, both the pro-inflammatory
and the programmed cell death pathways that are acti-
vated by TNF, and associated with tissue injury, are
largely mediated through TNFR1. The consequences
of TNFR2 signalling are less well characterized, but
TNFR2 has been shown to mediate signals that pro-
mote tissue repair and angiogenesis.
J Pathol 2008; 214: 149–160 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
JR Bradley
TNFR1 signals by recruitment of TNFR-associated-
death-domain protein (TRADD) [12]. TNFR1 is a
type I transmembrane protein, which in resting cells
is predominantly sequestered in the Golgi appara-
tus, from where it can be mobilized to the cell sur-
face.
The significance of the Golgi pool of TNFR1
molecules is unclear. One hypothesis is that it may act
as a reservoir to increase surface receptor expression
density, thereby sensitizing cells to the actions of
TNF. There is precedence for this idea in smooth
muscle cells, in which the TNF receptor family
member Fas localizes predominantly to the Golgi,
from where it can be translocated to the cell surface,
thereby sensitizing cells to Fas ligand-induced killing
[13].
Surface-expressed TNFR1 exist as trimers associ-
ated through pre-ligand assembly domains (PLADs)
[14], which reside within the membrane distal
cysteine-rich domain. In unstimulated receptors the
cytoplasmic domain is pre-associated with a cyto-
plasmic protein designated silencer of death domain
(SODD) [15]. SODD is thought to prevent constitu-
tive signalling of TNFR1, although mice congenitally
deficient in expression of the sodd gene display normal
TNFR1 signalling [16]. Both TNFR1 and SODD con-
tain ‘death domains’ (DDs), which are protein motifs
that interact with other DDs. SODD uses its DD to
bind to the DD contained within the cytosolic por-
tion of TNFR1, preventing signalling. TNF binding to
TNF-mediated inflammatory disease
TNFR1 may result in the release of SODD, allowing
binding of a different DD-containing cytoplasmic pro-
tein, TNFR-associated DD protein (TRADD). TRADD
initiates signalling by recruiting two additional pro-
teins, receptor interacting protein-1 (RIP-1), a ser-
ine/threonine kinase which binds to TRADD through
its own DD [17], and TNFR-associated factor-2
(TRAF-2) an E3 ubiquitin ligase [18]) that does not
contain a DD. Within minutes this complex is internal-
ized [12], and the TRADD–RIP-1–TRAF2 complex
is released from TNFR1. Inhibitors of this process can
interfere with signalling [19,20].
Subsequent signalling events involve recruitment
and activation of different mitogen activated protein
kinase kinase kinases (MAP3Ks)]. RIP-1 is thought
to mediate recruitment of MEKK-3 and transforming
growth factor-beta (TGFβ)-activated kinase (TAK)1,
which in turn, activate the β-subunit of the inhibitor
of κB (IκB)] kinase (IKK) complex [21,22], leading to
phosphorylation of IκB proteins, signalling IκB ubiq-
uitination and proteosome-mediated degradation. Cys-
tosolic IκB proteins from a complex with the NF-κB
family transcription factors, masking nuclear localiza-
tion signals within NF-κB, and IκB degradation allows
NF-κB to enter the nucleus and initiate gene transcrip-
tion.
TRAF2 can also contribute to NF-κB activation,
both through binding of the IKK complex [23] and
through recruitment of inhibitor of cellular apop-
tosis proteins (cIAP)-1 and -2. cIAPs have cas-
pase inhibitors that also have ubiquitin protein ligase
(E3)] activity and can participate in IκB degrada-
tion [24]. The TRADD–RIP-1–TRAF-2 complex can
also recruit apoptosis-signalling kinase-1 (ASK-1)], a
MAP3K that associates with TRAF2 [25] and activates
MAP2Ks, including MEK-4 and -6 [26,27]. These
MEKs phosphorylate and activate c-Jun N-terminal
kinases (JNKs) and p38 MAPKs. Activated JNKs
phosphorylate the amino terminal region of c-Jun, a
subunit of the transcription factor activating protein 1
(AP-1). Phosphorylation of the amino terminal region
of c-Jun by JNK is essential for interactions of this
protein with cAMP-response-element-binding-protein-
binding protein [CBP]/p300 and gene transcription.
TNFR1 can also interact with FAN (factor associated
with neutral SMase activation) to activate neutral sph-
ingomyelinase, which can generate ceramide from the
breakdown of plasma membrane sphingomyelin [28]
and initiate apoptosis through the mitochondrial path-
way [29].
In addition to mediating cell survival and pro-
inflammatory signals through NF-κB and AP-1,
TNFR1 can also initiate cell death signalling path-
ways. This involves the binding of Fas-associated
DD protein (FADD) to TRADD and the subsequent
recruitment of pro-caspase 8 by the TRADD–FADD
complex. Autocatalytic activation of bound pro-
caspase 8 releases activated caspase 8, which ini-
tiates apoptotis through cleavage and activation of
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
151
pro-caspase 3. The recruitment and activation of pro-
caspase 8 can be inhibited by cFLIP, and elevated
levels of cFLIP induced by NF-κB activation may pre-
vent the activation of this death pathway [30]. TNFR1
activates other signalling responses that are less clearly
defined at a molecular level. These include activa-
tion of the ras–raf–MEK1–ERK1,2 pathway [31] and
phosphatidylinositol-3 kinase (PI3K), which phospho-
rylates the membrane lipid phosphatidylinositol 4.5
diphosphate (PIP2 ), converting it to phosphatidylinos-
itol 3, 4, 5 triphosphate (PIP3 ). PIP3 activates PDK-1,
an enzyme that phosphorylates the kinase Akt, and
also activates PDK-2, a complex containing mam-
malian target of rapamycin (mTOR), rictor and SAPK-
interacting protein (Sin)1, which is also involved in
activation of Akt [32]. ERK-1, -2 and Akt are gen-
erally associated with cell survival and proliferation
[33].
The signalling pathways initiated by TNFR2 are
less clearly defined, but TNFR2 appears to sig-
nal both shared and opposing effects to TNFR1.
TNFR2 lacks an intracellular death domain, but can
interact with TRAFs. TRAF1 was initially identi-
fied as a novel 45 kDa protein that could be co-
immunoprecipitated with human TNFR2 transfected
into the murine interleukin-2-dependent cytotoxic T
cell line CT6, and also from CT6 cell lysates by a
GST fusion protein containing the region of human
TNFR2 required for signal transduction [34]. At
the same time, TRAF2 was identified as a novel
56 kDa protein by using the yeast two-hybrid sys-
tem to detect proteins that interact directly with the
cytoplasmic domain of hTNFR2. Despite the co-
immunoprecipitation studies, only a very weak interac-
tion between TRAF1 and the cytoplasmic domains of
hTNFR2 or mTNFR2 could be detected using the two-
hybrid system. This seeming contradiction was rec-
onciled by the observations that a strong heteromeric
interaction occurred between TRAF1 and TRAF2, and
that TRAF1 and TRAF2 could form homo- and het-
erotypic dimers. Consequently, TRAF1 and TRAF2
can associate with the cytoplasmic domain of TNFR2
as a heterodimeric complex in which only TRAF2 con-
tacts the receptor directly. However, despite inherent
strong TRAF2 binding activity, ligand-dependent acti-
vation of TNFR2 does not appear to deliver strong
TRAF2-dependent signals, and TNFR2 has since been
found to have a TRAF2-binding site with high inher-
ent signalling capabilities, designated T2bs-N, together
with a carboxyl-terminal TRAF2-binding site des-
ignated T2bs-C that prevents the delivery of sig-
nals from T2bs-N [35]. This may provide a mech-
anism for diverting TRAF2 from TNFR1 via T2bs-
C without inducing TRAF2-mediated signals. Bind-
ing of TNF to TNFR2 can also limit signalling by
c-IAP1-dependent ubiquination and degradation of
TRAF2 and ASK1, terminating MAP3K signalling
[36].
TNFR2 can also activate endothelial/epithelial tyro-
sine kinase (Etk), a cytosolic kinase implicated in
J Pathol 2008; 214: 149–160 DOI: 10.1002/path
152
cell adhesion, migration, proliferation and survival,
independently of TRAF2. Etk is a novel regulator of
epithelial cell junctions and mediates the TNF-induced
phosphatidylinositol 3-kinase (PI3K)–Akt angiogenic
pathway in vascular endothelial cells through Etk-
mediated cross-talk with vascular endothelial growth
factor receptor 2 (VEGFR2) [37]. TNF activates Etk
through TNFR2 in a TRAF2-independent manner.
TNFR2 associates with an inactive form of Etk in a
ligand-independent fashion through the C-terminal 16-
amino acid sequence of TNFR2 and multiple domains
of Etk. TNF is thought to induce a conformational
change in TNFR2 that triggers unfolding of the
closed, inactive form of Etk. In endothelial cells, TNF
induces assembly of a trimolecular complex contain-
ing TNFR2, Etk and vascular endothelial growth factor
receptor 2 (VEGFR2, also known as KDR or flk-1).
Within this complex, there is a coordinate recipro-
cal phosphorylation of Etk and VEGFR2, resulting in
PI3K activation [37]. The appearance of phosphory-
lated Etk is indicative of TNFR2 signalling [38].
The utilization of different signalling mechanisms
by TNFR1 and TNFR2 is consistent with the ability
of each receptor to signal distinct biological responses
in cultured cells. Ligation of TNFR1 is both nec-
essary and sufficient to induce cytotoxic and pro-
inflammatory TNF responses, whereas TNFR2 may
promote cell activation, migration or proliferation.
Under certain circumstances, TNFR2 may contribute
to TNFR1 responses, particularly at low concentra-
tions of TNF [39], consistent with the notion of ‘ligand
passing’, in which TNFR2 captures TNF and passes
it to TNFR1 [40]. Cooperation between the receptors
may also be explained by the ligand-induced formation
of TNF receptor heterocomplexes [41].
Regulation of TNF receptors
Most cell lines and primary tissues co-express both
TNF receptors, although TNFR2 is preferentially
expressed on cells of haematopoietic lineage [42]. TNF
receptor types show a much more limited pattern of
cellular expression in vivo, and are highly regulated
by ischaemic or inflammatory tissue injury. For exam-
ple, normal kidney appears largely devoid of TNFR2
molecules, and TNFR1 molecules are essentially con-
fined to microvascular and glomerular endothelial
cells. This restricted protein distribution is supported
by in situ hybridization studies for receptor-encoding
mRNA. In kidney allografts undergoing rejection or
ischaemic injury, TNFR1 is lost from the endothelium
and there is new expression of TNFR2 in renal tubu-
lar epithelial cells. This regulated expression of TNF
receptors, which is recognized to occur in a wide range
of tissues, is likely to result from changes in both the
rate of synthesis and shedding of receptors.
A number of stimuli, including TNF, IL-1, IL-10
and tissue plasminogen activator, increase expression
of TNFR2 through transcriptional activation, whereas
J Pathol 2008; 214: 149–160 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
JR Bradley
TNFR1 is more commonly down-regulated by these
stimuli [43–45]. The possibility of differential syn-
thesis of the receptors is further supported by charac-
terization of their promoter regions. The 5
-regulatory
region of TNFR1 possesses features of a housekeeping
promoter [46,47]. The inducibility of TNFR2 is sup-
ported by analysis of its promoter region, which has
a cAMP-response element and consensus elements for
a number of transcription factors, including NF-κB,
AP-1, IRF-1 and GAS [42]. An additional factor that
is known to influence expression of TNF receptors
is shedding from the cell surface. TNF-binding pro-
teins, later characterized as soluble forms of the two
molecular species of cell surface TNF receptors, were
first purified from normal human urine [48]. Inflam-
matory mediators are known to induce shedding of
TNFR1 from endothelial cells [49,50], and nitric oxide
and hydrogen peroxide have been implicated in the
activation of a metalloproteinase involved in shed-
ding of TNFR1 [51]. The TNF receptor-associated
periodic syndrome (TRAPS) is an autoinflammatory
syndrome characterized by episodes of fevers, with
severe localized inflammation [52]. TRAPS is associ-
ated with heterozygous mutations in the extracellular
domain of TNFR1, which are associated with receptor
misfolding, an inability to form soluble receptors and
altered signalling [53].
Cell biological effects of TNF in the
inflammatory response
Although TNF receptors are differentially expressed
on a wide range of cells and tissues, many of the pro-
inflammatory effects of TNF can be explained on the
basis of TNF’s effects on vascular endothelium and
endothelial leukocyte interactions. In response to TNF,
endothelial cells promote inflammation by displaying,
in a distinct temporal, spatial and anatomical pattern
[54–56], different combinations of adhesion molecules
for leukocytes, including E-selectin, intercellular adhe-
sion molecule-1 (ICAM-1) and vascular cell adhesion
molecule-1 (VCAM-1) [57,58]. In combination with
the release of chemokines (including IL-8, MCP-1
and IP-10) [59], these responses lead to recruitment
of different populations of leukocytes independent of
antigen recognition. In addition, many of the clas-
sical features of inflammation can be produced by
local effects of TNF on endothelial cells. TNF-induced
expression of cyclo-oxygenase 2 can increase EC pro-
duction of vasodilatory PGI2 resulting in vasodilata-
tion [60], causing ‘rubor’ and ‘calor’ through increased
local blood flow. ‘Tumour’ can result from TNF-
mediated increased vascular permeability, allowing the
increased trans-endothelial passage of fluid and macro-
molecules to create oedema. In addition, TNF-induced
expression of pro-coagulant proteins, such as tissue
factor, and down-regulation of anticoagulant protein,
such as thrombomodulin TNF, can cause intravascular
thrombosis [61].
TNF-mediated inflammatory disease
Physiological roles of TNF
One of the major biological roles of TNF is in the
host defence to bacterial, viral and parasitic infec-
tions. Physiologically, TNF is important for the normal
response to infection, but inappropriate or excessive
production can be harmful. TNF was originally identi-
fied as an endotoxin lipopolysaccharide (LPS)-induced
humoral mediator of murine cachexia, the syndrome
of anorexia, weight loss and protein wasting that com-
plicates cancer and chronic infection and inflammation
[62]. TNF was confirmed as the principal mediator of
the lethal effect of Escherichia coli-derived endotoxin
by demonstrating that passive immunization of mice
with rabbit anti-serum to TNF protected mice from its
lethality [63]. Baboons passively immunized with a
neutralizing monoclonal anti-TNF antibody and sub-
sequently infused with a lethal dose of live E. coli
were protected against shock, vital organ dysfunction,
persistent stress hormone release and death [64]. How-
ever, although a recombinant, soluble fusion protein
that combines an extracellular portion of the human
TNF receptor and the Fc portion of IgG (TNFR : Fc)
neutralizes TNF and prevents death in animal mod-
els of bacteraemia and endotoxaemia, in patients with
septic shock, treatment with TNFR : Fc did not reduce
mortality, and higher doses appeared to be associated
with increased mortality [65].
The importance of TNF as a modulator of the host
response to infection has been confirmed by stud-
ies using TNF receptor-deficient mice. Mice deficient
in TNFR1 are resistant to lethal dosages of either
lipopolysaccharides or Staphylococcus aureus entero-
toxin B, but have severely impaired clearance of the
intracellular bacterium Listeria monocytogenes and
readily succumb to this infection [66,67]. The activity
of TNF in endotoxin-induced lethal shock and innate
resistance to Listeria appears to be independent of
TNFR2 [68]. TNF has since been shown to be essen-
tial for the formation and maintenance of granulomas,
which limit dissemination of Listeria and other infec-
tions, including mycobacteria [69], and a number of
granulomatous infections have been reported in asso-
ciation with the use of TNF antagonists to treat human
inflammatory disease [70].
Evidence also supports a key role for TNF in para-
sitic and viral infections. TNF levels are increased in
the serum of children with uncomplicated Plasmod-
ium falciparum malaria, and markedly increased in
children with a fatal outcome from cerebral malaria,
leading to speculation that increased TNF production
is a normal host response to P. falciparum infection,
but that excessive levels of production may predispose
to cerebral malaria and a fatal outcome [8].
TNF appears to be central for the ICAM-1-
dependent recruitment of mononuclear cells and
microvascular damage that occurs in cerebral malaria
[71]. Anti-TNF therapy inhibits fever in cerebral
malaria [72] but does not improve survival [73]. Sup-
port for a role of TNF in host defences against viruses
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
153
has been provided by the existence of viruses encoding
TNF-binding proteins in their genome [74]. Further-
more, side-effects typically associated with viraemia,
including fever, rigors, headache and fatigue, were
observed in early trials of TNF in cancer patients
[75,76]. Indeed, although initially described as a
tumouricidal agent, toxicity has limited the role of
TNF as a chemotherapeutic agent for cancer. Further-
more, TNF may under some circumstances contribute
to carcinogenesis by promoting proliferation, inva-
sion and metastasis of tumour cells [77]. However,
isolated limb perfusion with TNF is of value in palli-
ating patients with metastatic sarcoma and melanoma
[78,79], providing tumour control and limb salvage for
the short survival of patients, and isolated hepatic per-
fusion with TNF has been used in patients with hepatic
metastases [80].
Although TNF blockade failed to be of benefit in
severe sepsis, the trials that were undertaken paved
the way for its use in chronic inflammatory diseases
such as rheumatoid arthritis, which in turn has high-
lighted the physiological roles of TNF in sepsis and
malignancy.
Therapeutic agents for TNF blockade
Three drugs, Humira (adalibumab), Remicade (inflix-
imab) and Enbrel (etanercept) are currently licensed
as TNF-blocking agents and used to treat rheumatoid
arthritis and other inflammatory diseases, including
ankylosing spondylitis and Crohn’s disease. Etaner-
cept is a recombinant human soluble fusion protein in
which TNFR2 is coupled to the Fc portion of IgG.
Infliximab is a human–murine chimeric IgG1 mon-
oclonal anti-TNF antibody. Adalibumab is a human
anti-human TNF antibody produced by phage display.
Other agents in clinical development have used PEGy-
lation to couple a large molecular weight polyethylene
glycol molecule to the TNF antagonist, with the aim of
prolonging the half-life. PEG–sTNFR1 is a pegylated
form of soluble TNFR1, and CDP-870 is a pegylated
Fab of the humanized anti-TNF antibody CDP-571.
Different anti-TNF therapies may have different
binding and pharmacokinetic profiles. The chimeric
monoclonal antibody infliximab may be a more potent
inhibitor of TNFR2 signalling than the TNFR2–Fc
fusion protein entarecept. Infliximab binds transmem-
brane TNF with higher avidity, forming more sta-
ble complexes and more effectively inhibiting the
actions of transmembrane TNF than entarecept [81].
Transmembrane TNF is superior to soluble TNF in
activating TNFR2 in various systems, including T
cell activation, thymocyte proliferation and granulo-
cyte/macrophage colony-stimulating factor production
[82]. Thus, under certain conditions infliximab may be
more effective at blocking signalling through TNF2
than etanercept.
The US Food and Drug Administration (FDA)
has reported certain serious, but uncommon, adverse
J Pathol 2008; 214: 149–160 DOI: 10.1002/path
154
events with all three approved anti-TNF agents
(http://www.fda.gov/ohrms/dockets/ac/03/briefing/
3930B1 01 B-TNF.Briefing.htm), including serious
bacterial infections, tuberculosis and certain oppor-
tunistic infections, demyelinating syndromes and sys-
temic lupus erythaematosus-like reactions. In con-
trolled studies of TNF blockade, more cases of lym-
phoma occurred among patients receiving the agents
than among control patients, and in open-labelled
uncontrolled studies the rate of malignancies in the
treatment group was several times higher than would
be expected in the general population. The avail-
able data suggest that these adverse reactions may be
related to TNF blockade and therefore represent class
effects of these agents.
Rheumatoid arthritis
Rheumatoid arthritis is a chronic autoimmune inflam-
matory disorder affecting approximately 1% of the
population, characterized by inflammation of syn-
ovial tissue, leading to progressive damage, erosion
of adjacent cartilage and bone and chronic disabil-
ity. The inflammation is associated with accumu-
lation of inflammatory cells, predominantly T cells
and macrophages, but also B cells, plasma cells and
dendritic cells. There is synovial hyperplasia and
angiogenesis is a prominent feature [83]. Many pro-
inflammatory cytokines, including IL-1, IL-6, TNF
and GM-CSF, are produced within the inflamed joint
[84].
Support for a dominant role of TNF was provided
by a number of in vitro and in vivo studies. Production
of a range of pro-inflammatory cytokines by cultured
cells from the joints of patients with rheumatoid arthri-
tis can be down-regulated by a neutralizing antibody
to TNF [85,86]. Neutralizing TNF with either anti-
TNF antibody or a recombinant soluble TNF recep-
tor ameliorates joint disease in a murine model of
collagen-induced arthritis [87–89]. Deleting TNF AU-
rich elements (AREs) from the mouse genome resulted
in profound temporal and spatial deregulation of TNF
production, characterized by the persistent accumula-
tion and decreased rates of decay of the mutant TNF
mRNA. This deregulation resulted in overexpression
of TNF and the development of chronic inflammatory
arthritis and inflammatory bowel disease [90].
An open Phase I/II clinical trial of a murine-human
chimeric neutralizing monoclonal antibody to TNF in
20 patients with active rheumatoid arthritis demon-
strated that the treatment was safe and well toler-
ated and resulted in significant clinical and laboratory
improvements [91]. The efficacy of anti-TNF treat-
ments in rheumatoid arthritis was subsequently con-
firmed in randomized controlled trials, which estab-
lished that methotrexate and anti-TNF treatment have
a synergistic effect, and demonstrated that long-
term treatment is feasible [92–98], although loss of
response may occur in about half of patients during
the first year [99].
J Pathol 2008; 214: 149–160 DOI: 10.1002/path
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
JR Bradley
Inflammatory bowel disease
TNF immunoreactivity is increased the lamina propria
in intestinal specimens from patients with Crohn’s
disease and ulcerative colitis [100,101], and mice
overexpressing TNF develop a Crohn’s disease-like
inflammatory bowel disease [90].
Infliximab has been shown to be effective in induc-
ing remission, and an effective maintenance ther-
apy for patients with Crohn’s disease with and
without fistulas [102,103]. A randomized controlled
trial demonstrated that the humanized anti-TNF anti-
body CDP571 was an effective for treatment of
patients with moderate to severe Crohn’s disease
[104], but subsequent studies showed that CDP571
is not effective for long-term treatment of unselected
patients with moderate to severe Crohn’s disease
[105].
A systemic review of randomized controlled trials of
TNF-blocking agents in patients with active Crohn’s
disease found that infliximab and CDP571, but not
etanercept, may be effective in inducing remission
[106].
The role of TNFα-blocking agents in ulcerative col-
itis is less clear, and recent studies have yielded con-
flicting results. A systematic review concluded that
in patients with moderate to severe ulcerative coli-
tis whose disease is refractory to conventional treat-
ment using corticosteroids and/or immunosuppres-
sive agents, infliximab is effective in inducing clin-
ical remission, inducing clinical response, promoting
mucosal healing and reducing the need for colectomy,
at least in the short term [107].
Ankylosing spondylitis
Ankylosing spondylitis is an inflammatory arthritis
that predominantly affects the spine and sacroiliac
joints. It occurs more commonly in patients with
Crohn’s disease. TNF has been detected in the sacro-
iliac joints of patients with ankylosing spondylitis
[108], particularly in early active disease [109], and
elevated serum levels of TNF correlate with disease
activity [110].
A randomized, double-blind trial of etanercept
showed that treatment with etanercept for 4 months
resulted in rapid, significant and sustained improve-
ment in patients with ankylosing spondylitis [111].
Subsequent studies have confirmed the efficacy and
safety of etanercept in patients with active ankylos-
ing spondlitis over 2 years of continuous treatment
[112,113], and have shown that etanercept is effec-
tive in patients with early onset ankylosing spondylitis
before the age of 18 [114].
Infliximab is also an effective agent in patients
with active ankylosing spondylitis, for inducing and
maintaining remission and readministration to treat
relapse after discontinuation of long-term therapy
[115,116].
TNF-mediated inflammatory disease
Psoriasis
Psoriasis is an inflammatory skin disorder, in which an
inflammatory cell infiltrate is associated with hyperk-
eratotic lesions, giving rise to typical psoriatic plaques.
TNF, TNFR1 and TNFR2 are upregulated in dermal
blood vessels in involved skin from patients with pso-
riasis [117,118].
Randomized trials showed that infliximab resulted
in a rapid and significant improvement in psoriatic
plaques [119,120]. Up to one-third of patients with
psoriasis develop an inflammatory arthritis, which
can affect both spinal and peripheral joints. Early
studies suggested a role for etanercept in the treatment
of psoriatic arthritis, and subsequent studies have
shown that infliximab, etanercept and adalimumab are
all effective treatments for the dermatological and
articular manifestations of psoriasis [121–124].
Disease of the central nervous system
In the central nervous system, TNF is produced pri-
marily by microglia and astrocytes in response to
a wide range of pathological processes, including
infection, inflammatory disease, ischaemia and trau-
matic injury [125]. However, TNF has been shown
to have both harmful and beneficial effects in the
injured brain [126]. Inhibition of TNF ameliorates
ischaemic brain injury in mice [127], whereas mice
lacking TNF are highly susceptible to experimen-
tal autoimmune encephalomyelitis, and treatment with
TNF dramatically reduces disease severity [128]. TNF-
mediated protection against experimental autoimmune
encephalomyelitis does not require TNFR1, although
TNFR1 appears to be necessary for detrimental effects
of TNF, which occur during the acute phase of the
disease [129]. In contrast, TNFR2 has been shown to
promote proliferation of oligodendrocyte progenitors
and remyelination in a neurotoxicant murine model of
demyelination [130]. Neutralization of TNF failed to
benefit patients with relapsing–remitting multiple scle-
rosis, and significantly increased exacerbations [131].
Cardiovascular disease
TNF has also been implicated in the pathogenesis
of a number of cardiovascular diseases, including
atherosclerosis, myocardial infarction, heart failure,
myocarditis and cardiac allograft rejection, and vas-
cular endothelial cell responses to TNF may underlie
the vascular pathology in many of these conditions.
However, clinical trials have demonstrated no clinical
benefit of TNF blockade in congestive cardiac failure.
This may be because TNFR1 and TNFR2 differen-
tially regulate cardiac responses to TNF. In transgenic
mice with TNF-induced cardiomyopathy, ablation of
the TNFR2 gene exacerbates heart failure and reduces
survival, whereas ablation of TNFR1 blunts heart fail-
ure and improves survival [132]. In cardiac allografts
either TNF receptor is capable of mediating a response
that will culminate in graft arterial disease [133].
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
155
Patients with chronic inflammatory conditions such
as rheumatoid arthritis have an increased incidence
of cardiovascular disease. Inflammatory mediators,
including TNF, have been implicated in this increased
cardiovascular risk, and there is some evidence that
anti-TNF therapy ameliorates this risk in patients with
rheumatoid arthritis [134].
Respiratory disease
TNF has been implicated in the pathophysiology of
many inflammatory lung diseases, including chronic
bronchitis, chronic obstructive pulmonary disease,
acute respiratory distress syndrome and asthma [135].
In asthma, TNF has been implicated in airway
inflammation and remodelling, and may play a role
in bronchial hyper-responsiveness. Leukocytes from
bronchiolar lavage of asthma patients have increased
release of TNF [136], and inhaled TNF increases air-
way responsiveness in normal subjects and is associ-
ated with a pulmonary neutrophil infiltration, assessed
by induced sputum. To date there are no random-
ized controlled trials of TNF blockade in asthma,
but patients with asthma who received infliximab for
rheumatoid arthritis have demonstrated a significant
improvement, and an open label uncontrolled study of
etanercept in 17 subjects with severe asthma demon-
strated an improvement in asthma symptoms, lung
function and bronchial hyper-responsiveness follow-
ing 12 weeks of entanercept [137]. A pilot study of
patients with refractory asthma provided evidence for
a role of TNF, and demonstrated a beneficial effects
of etanercept on markers of asthma control [138].
Renal disease
TNF has been implicated in the pathogenesis of many
renal diseases, including ischaemic renal injury, renal
transplant rejection and glomerulonephritis, which is
often part of a systemic vasculitis. In diseases associ-
ated with renal inflammation, different forms of TNF
blockade vary in their efficacy and adverse effects,
and these differences may be attributed to different
effects on signalling though TNF receptor subtypes. In
acute renal injury, TNFR2-mediated cell proliferation
may be important for tubular cell regeneration [38],
whereas in proliferative forms of glomerulonephri-
tis, TNFR1-mediated cytotoxicity and inhibition of
TNFR2-mediated cellular proliferation may be more
desirable.
TNFR2 is essential for the development of renal
injury in a model of immune complex glomeru-
lonephritis induced by anti-GBM antibody, raising the
possibility that selective blockade of TNFR2 may be a
promising strategy for treatment of immune-mediated
glomerulonephritis [139].
As discussed above, infliximab may be more effec-
tive at blocking signalling through TNFR2 than etan-
ercept. In support of this, infliximab is an effective
treatment for patients with refractory Wegener’s gran-
ulomatosis [140], in which lymphocyte activation and
J Pathol 2008; 214: 149–160 DOI: 10.1002/path
156
glomerular cell proliferation are important in patho-
genesis. In contrast, etanercept is not effective for the
maintenance of remission in patients with Wegener’s
granulomatosis, and its use is associated with an
increased incidence of solid tumours [141].
Other inflammatory diseases
As the potential role of TNF blockade has become
clear, its successful use has been reported in an
increasing number of inflammatory conditions. These
include juvenile rheumatoid arthritis [142]; therapy-
resistant sarcoidosis, a multisystemic disorder charac-
terized histologically by the presence of granuloma-
tous inflammation [143–145]; inflammatory myopa-
thies [146]; Behcet disease [147]; and inflammatory
eye disease [148].
Summary
Although the capacity of bacterial toxins to induce
tumour regression was first described at the end of
the nineteenth century, TNF was not identified as the
tumouricidal agent until 1975. TNF was cloned in
1984, and the last two decades have seen how molec-
ular and cellular biological techniques, combined with
in vivo studies, have unravelled the complexity of
TNF and its signalling pathways and the pathophys-
iological responses it triggers. This has led to an
understanding of its key role in inflammatory disease
and perhaps the most remarkable example of transla-
tional medicine, as scientists have collaborated with
clinicians and the pharmaceutical industry to develop
improved anti-inflammatory therapies. In turn, clinical
studies are providing valuable insights into the mech-
anism of action of TNF, allowing the science to return
to the laboratory to continue to address the many unan-
swered questions.
Acknowledgement
JRB is supported by the NIHR Cambridge Biomedical Research
Centre, UK.
Teaching materials
Power Point slides of the figures from this Review may
be found at the web address http://www.interscience.
wiley.com/jpages/0022-3417/suppmat/path.2287.html
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