Cytokines

describes classification of cytokines and also its role in brief. you can use this for a quick reference.

1. Cytokines Dr. Vasavi reddy

2. Introduction : Cytokines are diverse group of intercellular signalling low molecular weight proteins that provide a network controlling local and systemic immune and inflammatory responses but also wound healing, hematopoiesis and other biologic process. The term cytokine encompasses those cytokines secreted by lymphocytes ,substances formerly known as LYMPHOKINES, and those secreted by monocytes& macrophages substances formerly known as MONOKINES

3. Definition : Steve offenbacher 1996 defined cytokines as mediator molecules, which direct and regulate inflammation and wound healing. The term cytokine meaning the cell protein is reserved for molecules, which transmit information or signals from one cell to another. It is part of a fundamental cell-to-cell communication network. Okada and S. Murakami 1998 cytokines are small soluble proteins produced by a cell that alters the behavior or properties of another cell, locally or systemically.

4. CLASSIFICATION NISSENGARD NEWMAN First group : cytokines which serve as mediators of innate immunity e.g α , β , interferon, TNF, Il-6 Second group : cytokines that regulate the growth & differentiation of lymphocytes e.g Il 2,4 TGF β Third group : that regulate hematogenous activity e.g Gm csf , G csf Il-3,7 Fourth group : cytokines that share the common property of being activation of inflammatory cell function e.g gamma interferon JAN LINDHE Proinflammatory cytokines E.g. IL-1, IL-6 and TNF  Chemotactic cytokines E.g. IL-8  Lymphocytes signaling cytokines E.g. Cytokines released by Th1- IL-2, IFN. Cytokines released by Th2- IL-4,IL-5,IL-10 and IL-13.

5. Based on families

6. Receptors :

7. Mechanism of action: cytokine binds to its receptor on the cells and induces dimerization or polymerization of receptor polypeptides of the cell surface. This causes activation of intracellular signaling pathways (e.g. kinase cascades) resulting in the production of active transcription factors which migrate to the nucleus and bind to the enhancer region of gene, induced by that cytokine.

8. Functions: Basically cytokines interact with cells to cause: Activation (of metabolism, cellular synthesis etc) Proliferation or inhibition of proliferation Apoptosis Differentiation Chemotaxis.

9. General properties: Cytokine secretion brief, self limited, mRNA unstable Actions are pleiotropic and redundant Influence the synthesis and action of other cytokines Bind with high affinity to a specific membrane receptor External signals lead to regulation of receptors Cellular response to these include changes in gene expression Actions can be local or systemic

10. Interleukin 1: Interleukin –1 is a very potent multifunctional cytokine that appears to be a central regulator of the inflammatory and immune responses. IL-1 is a Pleotropic cytokine with a variety of activities. It includes osteoclast activating factor (OAF) because of stimulation of osteoclasts and lymphocyte activating factor (LAF) because of its ability to stimulate proliferation of phytohemagglutination -treated T-cells. It is secreted by monocytes, macrophages, B-cells, fibroblasts, neutrophils, and epithelial cells. Bacterial Lipopolysaccharide is a potent commonly used stimulus for IL-1 production. IL-1 synthesis is suppressed by several endogenous factors, such as Corticosteroids, Prostaglandins, Cytokines like IFN-  , IL-4. Some of the other cytokines share biologic activities with IL-1, most importantly IL-6 and TNF factor. There are 2 principal forms of IL-1 that have agonist activity, IL-1 , IL-1  , with a third ligand, IL-1 receptor agonist (IL-1ra) that functions as a competitive inhibitor. Two IL-1 receptors are found on the surface of the target cells, designated IL-1 receptor-1 and IL-1 receptor 2.

11. Biological activity: Lymphocyte activation, macrophage activation, Natural killer stimulation, Prostaglandin formation, Fever induction, Anorexia, Acute phase protein release, Adrenocorticotophin release, Corticosteroid release, Cytokine gene expression, Plasminogen activator, Endothelial cell activation, Tumor cell growth inhibition, and suppression of lipoprotein lipase gene expression.

12. Interleukin 2: IL-2 (  and  ) was originally called T-cell growth factor because of its effect on mitogen or antigen activating T-cells and is known to play a general role in immune responses. IL-2 also stimulates macrophage functional activity, modulates natural killer function and induces natural killer proliferation. It is secreted by Th cells and NK cells. Clinical aspects: Used in Tumors immunotherapy, either using IL-2 alone or in combination with in-vitro activated lymphokine-activated killer cells. The potential for IL-2 as a cancer treatment is based on activation of cells, which are cytotoxic to the tumor. Adverse effects: fever, chills, fatigue, nausea, vomiting, capillary leakage syndrome or vascular leakage syndrome, characterized by the accumulation of edema fluid in pleural cavities.

13. Interleukin 3: IL-3 is a distinct hematopoietic factor affecting multiple hematopoietic cell lineages. IL-3 also known as burst-promoting factor, B- cells stimulating factor, hemopoietic cell growth factor and multi colony stimulating factor is produced primarily by activated helper T type I and II cells. This molecule stimulates the growth of colonies of mast cells, neutrophils, macrophages, eosinophils, and megakaryocytes. It is secreted by activated helper T cells, NK cells. IL-3 acts as a link between the T- lymphocytes and mast cells of the immune system, and the hematopoietic system, which generates the accessory cells granulocytes, phagocytes, and platelets, which carry out repair and defense responses.

14. Interleukin 4: IL-4 originally called T-cell-derived B-cell growth factor (BCGF-1) because of its activation of B cells. Also called as migration inhibition factor. It is also play a role in the activation, proliferation and differentiation of B cells, T-cell growth, macrophage function, and growth of mast cells. IgE synthesis by B cells is also induced by IL-4. It is secreted by helper Tcells . Receptors for this cytokine found on T-cells, B-cells, mast cells, myeloid cells, fibroblasts, neuroblasts, stromal cells, endothelial cells and monocytes. Effects on macrophages: It can activate macrophage cytocidal function and increase macrophage expression of class II MHC proteins. It suppresses the synthesis of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF-  and activated monocytes.

15. Interleukin 5 Interleukin-5 is the name given to a lymphokine (a cytokine produced by lymphocytes). Coffman and colleges found that IgA enhancing factor was IL-5 when the protein is sequenced. Metcalf used the term eosinophil colony stimulatory factor to describe this cytokine. Thus initially known as B- cells growth and differentiation factor, IgA enhancing factor, eosinophil colony stimulating factor. The major function of IL-5 in humans is to stimulate the production of eosinophils. IL-5 not only increases the number of eosinophils but also has been reported to increase their function.

16. Interleukin 6: Interleukin-6 is a multifunctional cytokine produced by various cells such as activated monocytes or macrophages, endothelial cells, activated T-cells, and fibroblasts. Formerly these molecules were known as B- cells stimulatory factor II, interferon B2 and plasmacytoma growth factor. Its effect on B cells is to promote growth and facilitate maturation of the B cells causing immunoglobulin secretion. IL-6 increases in sites of gingival inflammation and plays a role in bone resorption.

17. Interleukin 7: Secreted by thymus, spleen and bone marrow stromal cells that functions as a growth factor for T and B cells precursors. It was formerly known as lymphopoitin 1 based on its capacity to influence early lymphopoiesis. IL-7 enhances the function of mature activated lymphocytic cells, particularly those with cytotoxic activity. At higher concentrations, IL-7 also increases macrophage cytotoxic activity and induces cytokine secretion by monocytes.

18. Interleukin 8: Interleukin-8 is Chemotactic for neutrophils, increases their adherence to the endothelium. In general these cytokines are produced by: 1. Antigen stimulated T lymphocytes 2. Mononuclear phagocytes, endothelial and epithelial cells, and fibroblasts that have been activated by other cytokines or LPS. 3. Platelets. All members of this family stimulate leukocytes and contribute to inflammatory responses.

19. Interleukin 9: Interleukin-9 is a heavily glycosylated polypeptide lymphokine with an apparent MW of 30000 to 40000. It is secreted by IL-2 activated T-cells and Hodgkin's lymphoma cells. It is a T cell growth factor, which acts in synergy with other cytokines.

20. Interleukin 10: IL-10 is an 18000 MW protein that is produced late in the activation process by Th2 cells, CD8 T cells, monocytes, keratinocytes and activated B cells. It was originally called cytokine synthesis inhibitory factor because of its ability to inhibit cytokine production by activated T-lymphocytes i.e., Th1 cells and NK cells. IL-10 inhibits the antigen presenting capacity of monocytes. IL-10 also synergies with other cytokines to stimulate proliferation of B cells and mucosal mast cells. Together with TGF beta it causes IgA production by B cells.

21. Interleukin 11: Biologic activities of IL-11: Growth promotion of a plasmacytoma cell line: Originally IL-11 was detected based on its ability to stimulate the proliferation of an IL-6 dependent mouse plasmacytoma cell line. The ability of IL-11 to support the growth of such a plasmacytoma cell line suggest that cytokine may be removed in the establishment and maintenance of plasmacytomas in vivo and may play an important role in the tumourogenesis . Hematopoietic colony stimulating activity: Alone, IL-11 cannot support the growth of megakaryocyte colonies but stimulates and increases in numbers, size of megakaryocyte colonies in combination with IL3. Therefore IL-11 is not a megakaryocyte colony stimulating factor but rather acts like a megakaryocyte potentiator, their results suggest that IL-11 may play an important role in megakaryocytopoiesis and possibly in vitro platelet production.

22. Interleukin 12: It was originally called cytotoxic lymphocytes maturation factor (CLMF) or NK cell stimulatory factors. It is produced predominantly on activation by B cells and macrophages. It acts synergistically with IL-2 to induce IFN-  by T-cells and NK cells It is a key factor in the development of Th1 cells, stimulating both their proliferation and differentiation. It suppresses Th2 dependent functions, such as the production of IL-4, IL-10, IgE antibodies. IL-12 also induces the production of GM-CSF, TNF, IL-16, IL-2.

23. Interleukin 13 The marked structural homology between IL-4 and IL-13 and the close juxtaposition of their genes on the chromosome suggest that gene duplication occurred. IL-13 is predominantly expressed in activated Th2 cells and regulates human B cell and monocytic activity. Interleukin 14 IL-14 is a 50-60 KD glycosylated cytokine otherwise known as the high mol wt B cell growth factor. IL-14 is thought to play a role in the development of B cell memory. It enhances the proliferation of activated B cells and inhibits the synthesis of immunoglobulin. It is produced by follicular dendritic cells and activated T cells. IL-14 receptors are found only in cells of the B cells lineage. IL-14, participates mainly in secondary humoral immune responses.

24. Interleukin 15 IL-15 is widely expressed in kidney, lung, liver, heart and bone marrow stroma. It is produced most abundantly by epithelial cells and monocytes, but not by T lymphocytes. It functions as a signal from non lymphoid cells for generating T cell dependent immune responses. Interleukin 16 IL-16 which was previously known as lymphocyte chemoattractant factor (LCF) is produced by lymphocyte and induces the directional migration of CD4+ T cells, eosinophils and monocytes. The chemoattractant effect of LCF is blocked by anti CD4 Fab fragments suggesting that CD4 or CD4 related molecules are required for the effects of LCF on target cells.

25. Interferons

26. Tumour necrosis factor: TNF is a principal mediator in the host inflammatory response. The main cell type secreting TNF is the mononuclear phagocyte. The main stimulus for release is the Lipopolysaccharide of bacterial cell walls. There are two structurally and functionally similar forms of TNF  and  but they differ biochemically. TNF  is 17 KD is derived from stimulated macrophages and appears to have significant stimulatory activity on the cytoxic T lymphocytes (CTL) responsible for lysing tumor or virally infected cells. TNF-  is a 25 KD glycoprotein derived from activated T cells with a 28% homology to TNF-   Form is occasionally known as lymphotoxin these virtually have similar actions, which includes CTL stimulation, osteoclast activation of PMNLs and antiviral activity. TNF also appears however to act synergistically with cytokines and induces release of IL-1.

27. Transforming growth factor β TGF  was initially discovered as a growth factor for fibroblasts and promotes wound healing. T lymphocytes produce TGF  . Humans express at least three forms of TGF  called TGF  -1, TGF  -2, TGF  -3. These are products of separate genes, but they all bind to 5 types of high affinity cell surface receptors. TGF  has anti proliferative effects on a wide variety of cell types including macrophages, endothelial cells and T and B-lymphocytes. TGF is a chemoattractant and promotes many functional activities of fibroblasts. TGF  is a potential mediator of inflammation because it is a product of activated macrophages, a potent chemoattractant for macrophages and can activate macrophages to produce IL-1. It is chemo attractive for neutrophils and monocytes and it stimulates monocyte expression of adhesion proteins

28. Chemokines:

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