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Cytokines
- 2. Cytokines are agroup 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. The activity ofcytokines 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 measurethe 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 InitiateCell-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 andtheir 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 NumerousBiological 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.
- 10. Distance Autocrine Endocrine Blood circulation Paracrine Nearby self Autocrine Cytokinebinds 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
- 11. Pleiotropic- phenomenon of differentactions produced by same cytokine on different targets
- 12. redundancy- different cytokinescan have the same effects on same targets.
- 13. Synergism - occurswhen the combined effect of two cytokines on cellular activity is greater than the additive effects of individual cytokines.
- 14. •Antagonism that is,the effects of one cytokine inhibit or offset the effects of another cytokine.
- 15. Cascade effect --- cytokinescan stimulate the production of other cytokines.
- 16. Cell growth Cell differentiation Celldeath Induce non-responsiveness to other cytokines/cells Induce responsiveness to other cytokines/cells Induce secretion of other cytokines Cytokine -mediated effects
- 17. Depending on thetype 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.
- 18. Cytokines can alsobe classified as pro-inflammatory and anti-inflammatory. .
- 19. While the pro-inflammatoryones 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
- 20. Major cytokines include: Lymphokines Interleukins(IL) Monokines Interferons (IFN) colony stimulating factors (CSF) Tumor Necrosis Factors-Alpha and Beta (TNF)
- 21. Interleukins - thatact 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.
- 23. A small groupof 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.
- 25. Cytokine Receptors FallWithin Five Families Receptors for the various cytokines are quite diverse structurally, but almost all belong to one of five families of receptor proteins:
- 26. The first fourreceptor 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.
- 27. the chemokine receptorshave 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
- 28. Diagram showing comparativestructural features of cytokine receptors of different families.
- 29. Cytokine signaling mechanisms Anumber 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.
- 30. Signal Transduction Initiated bycytokine 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
- 31. 1.- Binding ofcytokine 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
- 33. Biological functions ofcytokines 1.Take part in nonspecific immunity 2. Take part in specific immunity 3. Stimulate hematopoie sis 4. Take part in inflammator y reaction
- 34.
Editor's Notes
- #2 Fish appear to possess a repertoire of cytokines similar to those of mammals.
- #3 Your body is made up of trillions of cells. These cells are basic units of life; they carry out all the vital functions that keep you alive. Take the cells of your immune system, for instance. These cells are constantly sending out signals to let other cells know what's going on. To communicate, your immune cells use cytokines, which are a group of proteins secreted by cells of the immune system that act as chemical messengers. they are a group of molecules that act as messengers in inter-cellular communication. They are released mainly to stimulate an immune response when the cells detect any foreign substances in the blood.
- #5 Usually proteins or glycoproteins, that could regulate proliferation, diff erentiation, and maturation of immune system cells However, biochemical isolation and purification of cytokines was initially hampered because of their low concentrations in the culture supernatants and the absence of well-defi ned assay systems for individual cytokines. Using these pure cytokine preparations, researchers were able to identify cell lines whose growth depended on the presence of a particular cytokine, thus providing them with biological cytokine assay systems.
- #7 When cytokines are released from a cell, they attach to the receptors located on the outer cell membrane of target cells. This binding action triggers a chemical signal that is sent to the receptor cell, inducing it to perform a given activity. For instance, when a cell comes in contact with bacteria, it signals other cells of an imminent infection so that the immune system can work to combat the infection.
- #9 Although a variety of cells can secrete cytokines that instruct the immune system
- #10 Cytokines released from these cell types are capable of activating entire networks of interacting cells.
- #11 A particular cytokine may exhibit: Autocrine action by binding to receptor on the membrane of the same cell that secreted it. Paracrine action binding to receptors on a target cell in close proximity to the producer cell. Endocrine activity by traveling through circulation and acting on target cells in distant parts of the body.
- #16 Sequential and rationale release A series of components or networks, the output of each of which serves as the input for the next. A chemical or physiological process that occurs in successive stages, each of which is dependent on the preceding one, and often producing a cumulative effect: an enzymatic cascade
- #18 Both monocytes and lymphocytes are a type of WBCs, that help in regulating immunity.
- #19 Cytokines have been classified on the basis of their biological responses into pro or anti-inflammatory cytokines, depending on their effects on immunocytes .
- #23 Cytokines are structurally diverse and the extensive knoweledge now available of the structure of these molecules (alone and in complex with their receptors) is instrumental for rational classification, analysis of the evolution of cytokine system and therapeutic development.
- #27 The third and fourth receptor families are known as cytokine receptors type I and II
- #28 Finally,
- #30 Cytokines represent a diverse number of molecules. The super family of cytokine receptors more specifically refers to those cytokines that signal via the Jak-STAT pathway. These include Interleukins 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, & 15, and G-CSF, TNF and the interferons. Many growth factor signal pathways cross-communicate with the STAT pathway.