Cytokines

Cytokines

Messenger molecules of the immune & inflammatory system. Often produced and act on leukocytes (interleukins)
1. Pleiotrophic (can do more than one thing)-have effects simultaneously on more than one cell or have more than one action. ie they can act on many different cells producing many different effects
  1. Redundancy- several cytokines may have similar properties, actions and target cells. eg. IL-4 & !L-13/ IL-1a & IL-1b may be to avoid any potential lethal effect of gene loss or viral evasion of a single cytokine
Locally active- mostly acute medators ie paracrine-cell produces signal to induce changes in nearby cell not endocrine (in bloodstream). Act through receptors. Active at very low concs, work in cascade
Often act in vincinity in which they are produced. Are short lived. If they get into general circ=TROUBLE. IL-1/TNF= SHOCK. IL-2=vascular leakage. But very short half life in blood
Cytokine receptors
1. all cellls have receptor for atleast one cytokine/ growth factor
2. All receptors have an extracellular (cytokine-binding) domain & an intracellular (signal transduction) domain
  1. signal transduction= cell proliferation, diffentiaton, cell death, production of cytokines, expression of cell surface molecules
    1. Receptors may be simple eg IL-1R- extracellular & intracellular portion, transmem portion/ Complex eg IL-4 & IL-13= eg if virus found way to block IL-4- 2 pathways would still be present
3. Different cytokines may share receptor chains- IL-3, IL-5 & GM-CSF receptors share a common beta chain, but have different alpha chain.
4. Receptors may be shed from cells- cells can secrete cytokine receptors under certain conditions and bind cytokines extracellualely. At high level of cytokine, to prevent it from causing extensive inflammation damage to tissues can produce a soluble receptor which mop up excess cytokine and block its function. Very important in controlling cytokine activity in the general circ eg TNFR produced following stress/ shock STNFR blocks excessive TNF
Networks & cascades
1. Interferons
  1. Type I: IFNas and IFNb. Produced by and act on many cell types. Anti-viral and immunostimulatory effects. Type II: IFNy produced by T cells and NK cells upreg class I & II MHC and stimulate macrophage function
  2. Virus' trigger release
2. Some cytokines are heterohimers eg IL-12 is made up of p40 & p35 subunits. Rate limiting step is production of p35- many cells express p40, need p35.
3. Pro-inflammatory cytokines
  1. TNFa, IL-1, IL-6 (systemically found exception). TNF & IL-1 produce a local inflammatory response. IL-6 is a serum marker of inflammation used clinically to detect if patient is suffering from inflammation
    1. IL-1: 2 forms IL-1a & IL-1b. Only 27% homology but same activities and bind same receptors (to avoid having virus which can block both forms). IL-1Receptor type I on T cells, fibroblasts and endos. IL-1R type II on monocytes & macrophages. Induces IL-2 & IL-2R expression by T cells. Increases B cell prolif & Ig syn (can switch ona daptive)
    2. TNF receptors- 2 main ones: TNFRI (p55) induces apoptosis & TNFRII (p75) induces cell activation & proliferation
4. Anti-inflammatory cytokines
  1. IL-10 prevents TH1 cytokine production. IL-1RA (antagonist) inhibits action of IL-1
5. Chemokines
  1. leukocyte chemoattraction-attract leukocytes to site of inflammation. Leucocyte activation/degranulation, angiogenesis/angiostasis, tissue homeostasis/wound healing, lymphoid organ development, cell growth & metastasis (normal & tumour cells)
    1. Low molecular weight soluble molecules, some constitutive, involved in migration of leucocytes through lymphoid tissues. Other inducible in inflammation attracting leucocytes to sites of inflammation
  2. Families: 1. CXC/a chemokines- ELR: mainly attract neutrophils/non ELR: mainly attract monocytes.2. CC/b chemokines- attract lymphocytes, monocytes & eosinophils 3. CX3C chemokine: attracts lymphocytes & monocytes 4. C chemokine attracts lymphocytes
  3. Mech: Bind to proteoglycans/GAGs on endothelial cell luminal surface and form a stable conc gradient. Interact with receptors on 'rolling' leucocytes and induce activation of integrins (adhesion molecules which slow down leucocytes)-leads to stimulation of extravasation (move out of endothelial layer into tissues)
  4. Receptors: 7-pass transmembrane 'serpentine' receptors. Most specific for one or a few CC, CXC, C/CX3C chemokines. CXCR4 & CCR5 are co-receptors for HIV. Chemokines & their receptors have a major target for immune evasion by many virus' (they want to block chemokines)
T cell cytokines
1. Th1: some IL-2, IFNy, TNFb, GM-CSF & IL-3
2. Th2: some GM-CSF, IL-3, IL-4, 5, 6, 9, 10, 13.
Colony stimulating factors- CSFs
1. Act on blood stem cells to induce their growth. G-CSF (granulocytes), M-CSF (monocytes), GM-CSF (common precursor for G & M)
Therapeutics
1. GM-CSF used to speed neutophil recovery following bone marrow transplantation, chemo-or radiotherapy.
2. IL-10: used in psoriasis to dampen down immune system, IL-4 treats arthritis by dampening down immune sys
3. IL-12 used to treat asthma-TH2 mediated disease therefore if TH1 cytokine restore balance in asthma=decreased IgE)
4. IL2, IL12 & IFNa used in cancer immunotherapy to boost natural cell-mediated response
5. Anti-TNFa & blocking IL-12 function in rheumatoid arthritis because proinflammatory switched on excessively in rheumatoid arthritis
6. Anti TNF a also used in Crohn's disease, asthma & psoriasis
7. IL-8 & IL-12 blocks used in inflammatory bowel disease
8. Blocking TNFa & IL-1 in fever & sepsis (shock)

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	Created by tanitia.dooley almost 11 years ago