Important Cytokines

I. Growth Factors
1. Granulocyte Colony-Stimulating Factor (G-CSF) Also called Colony-stimulating factor and Pluri-poietin- Secreted by bone marrow stromal cells, macrophages and endothelial cells Functions Stimulates the development of neutrophils and other granulocytes Stimulates the proliferation and migration of endothelial cells 2. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) Also called Colony-stimulating factor and Pluri-poietin- Secreted by T cells, macrophages, endothelial cells and fibroblasts Functions: Stimulates the differentiation of granulocyte and monocyte progenitors Stimulates the growth of endothelial cells 3. Transforming Growth Factor - (TGF- ) Secreted by Platelets, macrophages, lymphocytes and mast cells Functions: Stimulate epithelial & mesenchymal cell growth Downregulates proinflammatory activities Induce class switch to IgA by plasma cells

II. Interleukins
1. IL-1 Secreted by monocytes, macrophages, dendritic cells, endothelial cells, B cells and other cell types (fibroblasts, keratinocytes, chondrocytes) Plays a major role in the development of an innate immune response Enhances NK cell activity Increases expression of ICAMS on vascular endothelial cells Chemotactically attracts macrophages and neutrophils Induces synthesis of acute-phase proteins by hepatocytes Induces fever by acting on the hypothalamus ((endogenous pyrogen) Role in Adaptive immune response Co-stimulates activation of T helper (Th) cells Promotes maturation and clonal expansion of B cells Additional roles Stimulation of the secretion of IL-6 and IL-8 Induction of expression of IL-2R 2. IL-2 Secreted by activated T cells Often referred to as the T Cell Growth Factor Role in the Innate immune response Stimulate growth of monocytes and macrophages Enhances proliferation and activation of NK cells Role in the Adaptive immune response Induces the proliferation, activation of antigen-primed T cells Acts on B cells to stimulate proliferation and antibody production

3. IL-3 Secreted by T cells, NK cells, eosinophils and mast cells Role in the Innate immune response Supports growth and differentiation of hematopoietic cells (myeloid) Stimulates growth and histamine production by mast cells Role in the Adaptive immune response Promotes growth of monocytes and B cells 4. IL-4 Secreted by T cells, NK cells and mast cells Role in the Innate immune response Regulates some stages of hematopoiesis Acts with other cytokines to stimulate mast cell proliferation (innate and adaptive) Role in the Adaptive immune response Role in the regulation of Th1-Th2 axis, pushes terminal differentiation of Th cells to Th2 (humoral arm Upregulates MHC II expression, antigen presentation and phagocytosis by macrophages Stimulates proliferation, differentiation and activation of antigen activated B cells Induces antibody class switching to IgE and IgG4 Acts to increase expression of MHC II on resting B cells Induces proliferation of thymocytes and T cells 5. IL-5 Secreted by T cells, mast cells and eosinophils Role in the Adaptive immune response: Promotes growth and differentiation of eosinophils (also helps innate) Co-stimulates proliferation and differentiation of activated B cells Induces antibody class switching to IgA 6. IL-6 Secreted by monocytes, macrophages, T and B cells, keratinocytes, fibroblasts, endothelial cells, and bone marrow stromal cells Plays a major role in an innate immune response Induces synthesis of acute phase proteins by hepatocytes Act on hypothalamus to induce fever (endogenous pyrogen) Promotes differentiation of myeloid stem cells Promotes terminal differentiation of proliferating B cells into plasma cells (antibody secreting cells) Stimulates antibody secretion by plasma cells 7. IL-7 Also called Lymphopoietin Secreted by Bone marrow and thymic stomal cells Role in the Adaptive immune response: Induces differentiation of lymphoid stem cells into progenitor B and T cells Increases expression of IL-2 and its receptor on resting T cells

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8. Il-8 Secreted by monocytes, macrophages, fibroblasts, endothelial cells, epithelial cells, keratinocytes, B and T cells Role in the Innate immune response: Acts as a chemokine to promote extravasation Recruit neutrophils to areas of injury Induce neutrophil adherence to endothelium Stimulates angiogenesis 9. IL-10 Secreted by monocytes, macrophages, keratinocytes and T cells Role in the Adaptive immune response Blocks production of cytokines by macrophage (downregulates cell mediated response Shuts down transcription of TNF- Downregulates inflammatory response Downregulates MHC II expression on antigen presenting cells 10. IL-12 Secreted by monocytes, macrophages, dendritic cells and B cells Plays a major role in Adaptive immune response Regulation of Th1:Th2 axis (promotes Th1 production) Co-stimulates differentiation of activated CD8+ cells into CTLs Role in both Innate and Adaptive immune response Stimulates proliferation of NK and LAK cells and antigen activated Th1 cells Stimulates the production of IFN- by NK cells and CTLs IL-13 Produced by T cells Anti-inflammatory Enhances B cell activation 12. IL-17 Produced by T cells; particularly those in the CD4 T cells in the peripheral blood Role in the Innate Response o Induces production of IL-6 and IL-8 o Enhances surface expression of ICAM-1 on human fibroblasts o Regulates expression of complement proteins o Chemotactic for neutrophils 13. IL-23 Produced by dendritic cells Activation of memory T cells

III. Tumor Necrosis Factors

1. Tumor Necrosis Factor- (TNF- ) Secreted by monocytes, macrophages, fibroblasts, B and T cells and NK cells Major role in innate response Induces cytokine secretion by inflammatory cell Increases expression of CAMS on vascular endothelial cells Increases expression of ligands on circulating neutrophil Causes smooth muscle contraction Induces production of acute phase proteins (C-reactive protein [CRP] and Mannose Binding Protein [MBP]

 Cytotoxic effect on tumor cells 2. Tumor Necrosis Factor - (TNF- ) Also known as Lymphotoxin (LT) Role in Innate immune response Has cytotoxic effects on tumor cells Enhances phagocytic activity of macrophages and neutrophils Inhibits proliferation of lymphoid and hematopoietic cells Role in Adaptive immune response Secreted by Th1 and CTL cells

IV. Interferons
1. Type I Interferons IFN- - Secreted by macrophages, monocytes, lymphocytes IFN- - Secreted by fibroblasts, epithelial cells IFN- - Secreted by keratinocytes All three promote the production of antiviral agents by uninfected cells Induces production of Double Stranded Activated Inhibitor of Translation (aka: DAI or RNA-dependent protein kinase) All three increase expression of MHC I on virally infected cells

2. Type II Interferon IFN- Secreted by Th1 cells, CTLs and NK cells Functions: Enhances intracellular killing by macrophages Increases expression of MHC I and II on many cells Regulates Th1-Th2 terminal differentiation Excess amounts inhibit proliferation of Th2 cells Excess amounts down humoral immune response Induces class switch to IgG2a (ADCC via Th1 axis) Blocks IL-4 induced class switch to IgE and IgG1 Mediates effects important in a Th1 driven DTH Promote the production of antiviral agents by uninfected cells by enhancing and inducing production of: 2,5 adenylate synthetase, Ribonucleases, Mx protein (also blocks capsid assembly)

V. Chemokines
1. RANTES Regulated upon Activation, Normal T-cell Expressed and Secreted Functions: Enhances extravasation by promoting chemotaxis of monocytes, basophils and eosinophils 2. MIP-1 , MIP-1 Monocyte/Macrophage Inflammatory Proteins Functions: Enhances extravasation by promoting chemotaxis of monocytes and macrophages