Cytokines

1. Cytokines

2. CYTOKINES • Definition: • Cytokines are a diverse group of non-antibody proteins that act as mediators between cells. ( they are chemical molecules). • They were initially identified as products of immune cells that act as mediators and regulators of immune processes but many cytokines are now known to be produced by cells other than immune cells and they can have effects on non-immune cells as well. • Cytokines are currently being used clinically as biological response modifiers for the treatment of various disorders.

3. CYTOKINES • The term cytokine is a general term used to describe a large group of proteins but there are other terms that are commonly used to describe particular kinds of cytokines. • These include: • Monokines (cytokines produced by mononuclear phagocytic cells). • Lymphokines (cytokines produced by activated lymphocytes, especially Th cells). • Interleukins (cytokines that acts as mediators between leukocytes). • Chemokines (small cytokines primarily responsible for leukocyte migration).

4. Cytokines are not typically stored as preformed proteins. Rather their synthesis is initiated by gene transcription and their mRNAs are short lived. • They are produced as needed in immune responses. • Cytokines regulate the intensity and duration of the immune response by stimulating or inhibiting the activation, proliferation, and/or differentiation of various cells, by regulating the secretion of other cytokines or of antibodies, or in some cases by actually inducing programmed cell death in the target cell.

6. Chemical signaling • Cytokines bind to specific receptors on target cells with high affinity and the cells that respond to a cytokine are either: • The same cell that secreted cytokine (autocrine). • A nearby cell (paracrine) or • A distant cell reached through the circulation (endocrine). • Cellular responses to cytokines are generally slow (hours) because they require new mRNA and protein synthesis.

8. The Functions of Cytokines • Cytokine signaling is very flexible and can induce both protective and damaging responses. • One cytokine often influences the synthesis of other cytokines.

9. Action of Cytokines • Pleiotropy • Affects multiple cell types • Redundancy • Multiple cytokines affects cells of the same type • Synergy • Cytokines acting in concert on the same cell • Antagonism • Competing actions • Cascading • Cytokines acting sequentially

12. Types of Cytokines’ receptors • Receptors for cytokines are heterodimers (sometimes heterotrimers) many of which can be grouped into families based on common structural features; one subunit is common to all members of a given family. • Different cytokine receptors have specific cytokine-binding chains usually associated with a common signaling chain.

13. Types of Cytokines’ receptors • According to the extracellular cytokine-binding domain, cytokine receptors are divided into 5 families: • Class I cytokine receptors(hematopoietin family):heterodimers • Class II cytokine receptors (interferon family): heterodimers • TNF receptor family • Immunoglobulin(Ig) superfamily receptors(IL-1)rare • Chemokinereceptors(seven-transmembrane a-helical receptors)

15. Cytokine networks • Cytokines function as part of a larger inter-related system of proteins and signaling cascades, the cytokine network. • These are complex interactions in which different cells can respond differently to the same cytokine depending upon other signals received by the cell. • Although the focus of most research has been on the production and action of cytokines on cells of the immune system, it is important to remember that many of them have effects on other cells and organ systems.

16. A schematic diagram showing some of the interactions in the cytokine network Figure 5A

17. A schematic diagram showing some of the interactions in the cytokine network Figure 5B

18. A schematic diagram showing some of the interactions in the cytokine network Figure 5C

19. Cytokine networks (Cont) • In fact, the cytokine network is quite complex and represents a series of overlapping and inter-related connections amongst cytokines. • Within this network: • One cytokine may induce or suppress its own synthesis, • Induce or suppress the synthesis of other cytokines, • Induce or suppress synthesis of cytokine receptors (both its own and other cytokine Rs), • Antagonize or synergize with other cytokines.

21. Categories of cytokines • Cytokines can be grouped into different categories based on their functions or their source but it is important to remember that because they can be produced by many different cells and act on many different cells, any attempt to categorize them will be subject to limitations.

22. Categories of cytokines

23. Categories of cytokines

24. Interleukin 1 family: Cytokines of the interleukin 1 (IL-1) family are typically secreted very early in the immune response by dendritic cells and monocytes or macrophages. IL-1 secretion is stimulated by recognition of viral, parasitic, or bacterial antigens by innate immune receptors. IL-1 family members are generally Proinflammatory, meaning that they induce an increase in the capillary permeability at the site of cytokine secretion, along with an amplification of the level of leukocyte migration into the infected tissues.

25. Hematopoietin (Class 1 Cytokine) family • Those are: • GM-CSF (Granulocyte-macrophage colony-stimulating factor):promotes the differentiation of bone marrow progenitors. • M-CSF( Monocyte-colony stimulating factor): promotes growth and differentiation of progenitors into monocytes and macrophages . • G-CSF:(also known as pluripoietin): promotes production of PMNs • IL-1,IL-3, IL-5, IL-6, IL-7, erythropoietin, Produced by bone marrow cells and leukocytes

27. Interferon (Class II Cytokine ) family Type I interferon:afamily of about 20 related proteins, and interferon-Beta, which are secreted by activated macrophages and dendritic cells, as well as by virus-infected cells. Interferons alpha and beta are also secreted by virally infected cells after recognition of viral components by pattern recognition receptors (PRRs) located either at the cell surface, or inside the cell

28. Type II interferon OR interferon-(gamma), is produced by activated T and NK cells. Interferon-(gamma) is a powerful modulator of the adaptive immune response, biasing T cell help toward the TH1 type and inducing the activation of macrophages, with subsequent destruction of any intracellular pathogens and the differentiation of cytotoxic T cells. All three interferons increase the expression of MHC complex proteins on the surface of cells, thus enhancing their antigen-presentation capabilities.

29. INF-Y Figure 2

31. In addition, a third class of interferons, the so-called interferon-, or type III Interferon family, was discovered in 2003. There are currently three members of this family: interferon-1 (IL-29), interferon-2 (IL-28A), and interferon-3 (IL-28B). Like Type I interferons, the Type III interferons up-regulate the expression of genes controlling viral replication and host cell proliferation.

32. Tumor Necrosis Family (TNF) • TNF-alpha:is produced by activated macrophages is response to microbes, especially theLipopolysaccharide(LPS) of Gram negative bacteria. • It is an important mediator of acute inflammation. • It mediates the recruitment of neutrophilsand macrophages to sites of infection by stimulating endothelial cells to produce adhesion molecules and by producing Chemokines which are chemotactic cytokines. • TNF- α also acts on the hypothalamus to produce fever and it promotes the production of acute phase proteins • TNF-beta (Lymphotoxin-alpha) : is activited by lymphocytes and bind to neutrophils,endothelial cells and osteoclasts(bone cells) • CD40L: is a cytokine expressed on the surface of T-cell that is required to signal for B-cell differentiation. • FasLigand (FasL),or CD95: induces apoptosis

34. Interleukin 17 family The most recently described family of cytokines, the IL-17 family, includes interleukins 17A, 17B, 17C, 17D, and 17F. IL-17 receptors are found on neutrophils, keratinocytes, and other non lymphoid cells. Members of the IL-17 family therefore appear to occupy a location at the interface of innate and adaptive immunity. IL-17 is produced by Th17 cells and its overexpression has been associated with autoimmune disease including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

36. Chemokines family Chemokines are a structurally related family of small cytokines that bind to cell-surface receptors and induce the movement of leukocytes up a concentration gradient and toward the chemokine source. This soluble factor-directed cell movement is known as chemotaxis, and molecules that can elicit such movement are referred to as chemoattractants

37. TGF-β • Transforming growth factor beta is produced by T cells and many other cell types. • It is primarily an inhibitory cytokine. • It inhibits the proliferation of T cells and the activation of macrophages. • It also acts on PMNs and endothelial cells to block the effects of pro-inflammatory cytokines

38. Categories of cytokines (IL-2) Figure 3

39. each subpopulation can exert inhibitory influences on the other