Cytokines & Adhesion molecules

Course 8

Denitions & Nomenclature

monokines lymphokines cytokines interleukins = IL-n
biologic response modiers

polypeptides produced in response to microbes/Ag that regulate the immune response

Abbas, Cellular & Molecular Immunology, 2007

Denitions & Nomenclature

Text

General properties
- secretion is brief & self-limited event

CYTOKINES

- actions are pleiotropic and redundant - inuence the synthesis of other cytokines - cascades - actions are local and systemic (autocrine-paracrine-endocrine) - initiate actions by binding to specic membrane receptors on target cells - actions are regulated by external signals - actions induce gene expression resulting in acquisition of new functions/cell proliferation - induced cell responses are strictly regulated by feedback inhibitory mechanisms

Abbas, Cellular & Molecular Immunology, 2007

Functional categories

Abbas, Cellular & Molecular Immunology, 2007

Cytokine receptors - Type 1 (hemopoietin)

- 2x cysteine residues - Trp-Ser-X-Trp-Ser (WSXWS) - binds type 1 cytokines - induce Jak/STAT cell signaling IL-r CSF-r Neuropeptide-r

Abbas, Cellular & Molecular Immunology, 2007

Cytokine receptors - Type II

- 4x cysteine residues - 2 extracellular domains - no WSXWS - binds type 1 cytokines - induce Jak/STAT cell signaling IL-r IFN-r

Abbas, Cellular & Molecular Immunology, 2007

Cytokine receptors - IL-1 receptor

- Toll-like/IL-1 (TIR) - Th1 - activatory IL-1 - Th2 - inhibitory IL-1 - induce Jak/STAT cell signaling - requires IL-1RAP for signal tr. IL-1

Abbas, Cellular & Molecular Immunology, 2007

Cytokine receptors - TNF receptor

- large family of proteins * - Cys-rich domains - induce apoptosis - TRAF sign. pathway

TNF

* - some of which are NOT cytokines receptors

Abbas, Cellular & Molecular Immunology, 2007

Cytokine receptors - TNF receptor

- large family of proteins * - Cys-rich domains - induce apoptosis - TRAF sign. pathway

TNF

* - some of which are NOT cytokines receptors

Abbas, Cellular & Molecular Immunology, 2007

Cytokine receptors - serpentine receptors

- 7 transmb. alpha-helical r - G-protein coupled r - induce apoptosis

Chemokines

* - some of which are NOT cytokines receptors

Role of cytokines
MEDIATION OF

INNATE immunity TNF; IL-1 Chemokines (CCL) IL-12; Type 1 - IFNs IL-10; IL-6; IL-15 IL-23; IL-27 HEMATOPOIESIS c-KIT ligand Epo IL-7; IL-3 GM-CSF

ADAPTIVE immunity
IL-2; IL-4; IFN-gamma TGF-beta; IL-13; IL-17; IL-5

Role of cytokines
MEDIATION OF

INNATE immunity TNF; IL-1 Chemokines (CCL) IL-12; Type 1 - IFNs IL-10; IL-6; IL-15 IL-23; IL-27 HEMATOPOIESIS c-KIT ligand Epo IL-7; IL-3 GM-CSF

ADAPTIVE immunity
IL-2; IL-4; IFN-gamma TGF-beta; IL-13; IL-17; IL-5

Role of cytokines
MEDIATION OF

INNATE immunity TNF; IL-1 Chemokines (CCL) IL-12; Type 1 - IFNs IL-10; IL-6; IL-15 IL-23; IL-27 HEMATOPOIESIS c-KIT ligand Epo IL-7; IL-3 GM-CSF

ADAPTIVE immunity
IL-2; IL-4; IFN-gamma TGF-beta; IL-13; IL-17; IL-5

Role of cytokines
MEDIATION OF

INNATE immunity TNF; IL-1 Chemokines (CCL) IL-12; Type 1 - IFNs IL-10; IL-6; IL-15 IL-23; IL-27 HEMATOPOIESIS c-KIT ligand Epo IL-7; IL-3 GM-CSF

ADAPTIVE immunity
IL-2; IL-4; IFN-gamma TGF-beta; IL-13; IL-17; IL-5

Tumor Necrosis Factor (TNF)

- No. 1 mediator of inamation in response to G(-) bacteria - Responsible for the majority of systemic complications in infection - No.1 source are activated mononuclear phagocytes - No. 1 function - recruitment of neutrophils and monocytes into sites of infection - induces expression of selectins/integrins/chemokines in the endothelial cells - In septic shock - prime inducer of fever (hypothalamus) - high circulating levels - major methabolic disturbances (severe hypoglicemia) - high circulating levels - muscle and fat cells wasting - cachexia

Tumor Necrosis Factor (TNF)

Interleukin 12 (IL-12)

- No. 1 mediator of early innate immune response to intracellular microbes - stimulates the production of IFN-gamma by NK and T-cells - together with IFN-gamma promotes differentiation of CD4Tcells into IFN(Th1) cells - Enhances the cytotoxic function of NK and CD8 Tcells (CTLs)

Interleukin 12 (IL-12)

Chemokines
- regulators of lymphocyte trafking from blood to tissue - recruit immune cells to the site of injury/infection - regulate the trafc of lymphocyte through lymphoid organs

Numer/location of N-Cys residue

Chemokines
- regulators of lymphocyte trafking from blood to tissue - recruit immune cells to the site of injury/infection - regulate the trafc of lymphocyte through lymphoid organs

Numer/location of N-Cys residue

C chemo

CC chemo

CXC chemo

CX3C chemo

http://artnscience.us/peripheral-lt.htmlxt

Leukocyte recruitment - infection

Chemokines - most important functions

MOVIE

http://artnscience.us/peripheral-lt.htmlxt

Leukocyte recruitment - infection

Chemokines - most important functions

MOVIE

http://artnscience.us/peripheral-lt.htmlxt

Leukocyte recruitment - infection

Chemokines - most important functions

MOVIE

http://artnscience.us/peripheral-lt.htmlxt

Leukocyte recruitment - infection

Chemokines - most important functions

MOVIE

http://artnscience.us/peripheral-lt.htmlxt

Leukocyte recruitment - infection

Chemokines - most important functions

MOVIE

http://artnscience.us/peripheral-lt.htmlxt

Leukocyte recruitment - infection

Chemokines - most important functions

MOVIE

http://artnscience.us/peripheral-lt.htmlxt

Lymphocyte trafking - adaptive immune response

Chemokines - most important functions

http://artnscience.us/peripheral-lt.htmlxt

Lymphocyte trafking - adaptive immune response

Chemokines - most important functions

http://artnscience.us/peripheral-lt.htmlxt

Lymphocyte trafking - adaptive immune response

Chemokines - most important functions

Abbas, Cellular & Molecular Immunology, 2007

Interleukin 2 (IL-2)
- key player (required) for survival and function of T-regulatory cells - stimulates survival, proliferation and differentiation of Ag-activated T-cells - promotes proliferation and differentiation of NK cells

Abbas, Cellular & Molecular Immunology, 2007

Interleukin 2 (IL-2)
- key player (required) for survival and function of T-regulatory cells - stimulates survival, proliferation and differentiation of Ag-activated T-cells - promotes proliferation and differentiation of NK cells

Interleukin 4 (IL-4)
- major stimulus for production of IgE Ab - key player in the development of Th2-cells from naive CD4helper Tcells - signature cytokine - functions as an autocrine growth factor for Th2-cells - +IL-13 functions to activate macrophages by an alternate (non-IFNgamma) mechanism

Interferon gamma (IFN-gamma)

- principal macrophage-activating cytokine - produced by CD4, CD8 and NK cells - promotes differentiation of CD4 T cells into Th1-cells - stimulates expression of MHC-I/II + costimulation on APCs

Transforming growth factor beta (TGF-beta)

- Principal action - inhibition of lymphocyte activation/proliferation - stimulates production of IgA Ab - skews B cells to this isotype - can induce apoptosis (SMAD or DAXX) - +IL-13 functions to activate macrophages by an alternate (non-IFNgamma) mechanism

Stem cell factor (c-KIT ligand)

- interacts with c-KIT (tyrosine kinase membrane receptor) present on stem cells - required for life (knock-out with c-KIT incompatible with life) - c-KIT rst described 1987 (Axel Ulrich)

Abbas, Cellular & Molecular Immunology, 2007

Other cytokines in control of hematopoiesis

Abbas, Cellular & Molecular Immunology, 2007

Take home message

- proteins that mediate crucial processes of innate/adaptive immunity - produced in response to inamation - act in a autocrine/paracrine/endocrine fashion - actions are mediated by high afnity receptors engaging Jak/STAT; TIR/IRAK; TRAF pathways - TNF/IL-1 (acute inamation to microbes); Type 1 IFNs (antiviral citokines); IL-10 (inhibit DCs) - IL-12 stimulate production of IFN-gamma inside macrophages - IL-2 - Tcell growth factor; IL-4 (development of Th2 Tcells); IL-5 (eosinophil activator) - TGF-beta (T-cell inhibitor); IL-13 (IgE production) - c-KIT Ligand/IL-7 - key roles in hematopoiesis - excessive production of cytokines leads to pathologic consequences - administration of cytokine inhibitors - potential approach to modify biologic response