Cytokines

cytokines,attributes,mode of action

1. Cytokines Abisha.S.J MFT16085

2. Definition Cytokines are a group of proteins made by the immune system that act as chemical messengers . Different cytokines, including chemokines , interferons , interleukins, lymphokines and tumor necrosis factor

3. Cytokines / immunocytokines (Greek , cyto =‘cell’ & kinos =‘movement’) are low molecular weight regulatory proteins or glycoproteins secreted by white blood cells and various other cells in the body in response to a number of stimuli. role in cell-to-cell communication Their major functions are to mediate and regulate immune response and inflammatory reactions.

4. History The activity of cytokines was first recognized in the mid-1960s , when supernatants derived from in vitro cultures of lymphocytes were found to contain soluble factors. The advent of hybridoma technology allowed the production of artificially generated T-cell tumors that constitutively produced IL-2, allowing for its purification and characterization . Gene cloning techniques developed during the 1970s and 1980s then made it possible to generate pure cytokines by expressing the proteins from cloned genes derived from hybridomas or from normal leukocytes, after transfection into bacterial or yeast cells.

5. ELISA assays measure the concentrations of cytokines in solution. Elispot assays quantitate the cytokines secreted by individual cells. cytokine-specific antibodies can be used to identify cytokine-secreting cells using intracellular cytokine staining followed by flow cytometry or immuno -fluorescence microscopy

6. How Cytokines Initiate Cell-to-Cell Signaling ? Cytokines act only on cells bearing specific receptors Binding triggering signal-transduction pathways alter gene expression in the target cells.

7. The cytokines and their fully assembled receptors exhibit very high affinity for each other and deliver intracellular signals . The cytokines and their receptors exhibit very high affinity for each other, with dissociation constants ranging from 10 –10 to 10 –12 M . Because their affinities are so high, cytokines can mediate biological effects at picomolar concentrations

8. Cytokines Have Numerous Biological Functions The principal producers are TH cells,dendritic cells, and macrophages . Cytokines released from these cell types are capable of activating entire networks of interacting cells. Among the numerous physiological responses that require cytokine involvement are the generation of cellular and humoral immune responses, the induction of the inflammatory response , the regulation of hematopoiesis , and wound healing.

9. Distance Autocrine Endocrine Blood circulation Paracrine Nearby self Autocrine Cytokine binds to receptor on cell that secreted it. Paracrine Cytokine binds to receptors on near by cells. Endocrine Cytokine binds cells in distant parts of the body A cytokine may act in 3 ways

10. Attributes Pleiotropic - phenomenon of different actions produced by same cytokine on different targets

11. redundancy- different cytokines can have the same effects on same targets.

12. Synergism  - occurs when the combined effect of two cytokines on cellular activity is greater than the additive effects of individual cytokines.

13. Antagonism that is, the effects of one cytokine inhibit or offset the effects of another cytokine.

14. Cascade effect Cascade effect --- cytokines can stimulate the production of other cytokines.

15. Cell growth Cell differentiation Cell death Induce non-responsiveness to other cytokines/cells Induce responsiveness to other cytokines/cells Induce secretion of other cytokines Cytokine -mediated effects

16. Classification Depending on the type of cell involved in the production of cytokines two major types; monokines and lymphokines . The former are secreted only by monocytes , while the later are released by lymphocytes .

17. Cytokines can also be classified as pro-inflammatory and anti-inflammatory . .

18. While the pro-inflammatory ones induce inflammation in response to tissue injury. The function of anti-inflammatory cytokines {(IL-4), (IL-10), and (IL-13)} is exactly the opposite . Their purpose is to lower the inflammatory response

19. Major cytokines include: Lymphokines Interleukins (IL) Monokines Interferons (IFN) colony stimulating factors (CSF) Tumor Necrosis Factors-Alpha and Beta (TNF)

20. Interleukins - that act as mediators between leukocytes. The vast majority of these are produced by T-helper cells. Lymphokines   - produced by lymphocytes. Monokines  - produced exclusively by monocytes . Interferons  - involved in antiviral responses. Colony Stimulating Factors  - support the growth of cells blood cell . Chemokines - mediate chemoattraction ( chemotaxis ) between cells.

21. Structure of cytokines

22. A small group of cytokines (IL1a, IL1b and IL18) have a beta structure characterised by a typical b-trefoil fold. A second and larger group (including TNFa , TNFb , CD40L, OX40L, Trail and Rankl ) also have a separate and distinctive beta structure (so called jelly roll fold ) characterised by a non covalent, trimeric assembly The largest family of non- chemokine cytokines have a alpha structure (so called four-helical fold ) and exhibit wide variations of this fold.

23. Cytokine receptor Cytokine Receptors Fall Within Five Families Receptors for the various cytokines are quite diverse structurally, but almost all belong to one of five families of receptor proteins:

24. The first four receptor families include single-pass transmembrane proteins whose extracellular moieties have complex multidomain structures and are all beta proteins The first family comprises proteins whose ecto domain contains Ig -type domains , the second one members of the TNF receptor family, proteins that, like-their ligands , these receptor assemble in homotrimeric structures.

25. the chemokine receptors have a structure different from that of all other cytokine receptors. These proteins are seven-pass transmebrane proteins and work as classic G-protein coupled receptors

26. Diagram showing comparative structural features of cytokine receptors of different families .

27. Cytokine signaling mechanisms A number of cytokine receptors signal via the JAK/STAT pathway. These include the receptors for IL2, IL-3, IL-4, IL-6, IL-10, IL-12 and IFN- γ γγ γ. Cytokine receptor subunits are associated with JAK kinases .

28. Signal Transduction Initiated by cytokine binding Activates JAK (Janus kinase ) Phosphorylation of tyrosine Binding of STAT(Signal transducers and activators of transcription ) Translocation of STAT to cell’s DNA Transcription of specific target genes

29. 1.- Binding of cytokine causes dimerization of receptors and activation of JAK kinases . 2.- Activated JAK kinases phosphorylate receptor sites and create docking sites for STAT molecules. JAK = Janus Kinase - OR - Just Another Kinase STAT = Signal Transducers and Activators of Transcription

30. Biological functions of cytokines

31. Immunology by Kuby http://pathmicro.med.sc.edu/mobile/m.immuno-13.htm http://www.rndsystems.com/research_topic.aspx?r=14 http://www.ebioscience.com/resources/pathways/cytokine-network.htm http://www.prospecbio.com/Cytokines http://www.sinobiological.com/What-Is-Cytokine-Cytokine-Definition-a-5796.html References

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