Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted de novo in response to immune stimuli, and usually act briefly, locally, at very low concentrations (the exception being endocrine action at distant cells). Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Table Immune Cytokines.
Responses to cytokines include:
a) up- or down-regulation of the expression of membrane proteins (including cytokine receptors),
b) secretion of effector molecules: histamine release; antibody secretion - IgA, IgG1, and IgE synthesis; IL-1 synthesis; cytokine production; MHC Class II; and CAM expression
c) cellular proliferation
d) chemotaxis of neutrophils, monocytes, and T cells
e) cellular differentiation
h) death of tumor cells
i) elimination of pathogens
Cytokines are classified according to the cells that produce them:
a) Lymphokines - lymphocytes
b) Monokine - monocytes,
c) Chemokine - chemotactic activities
d) Interleukin - manufactured by one leukocyte to act on other leukocytes.
The cells that produce cytokines include B-, T-, DC-, NK-, Tc-, Th-, Th1-, Th2-, endothelial, mast, plasma, progenitor, marrow stroma, thymus stroma, and tumor cells, along with fibroblasts, leukocytes, monocytes, and macrophages
Cytokine function may be targetted at:
a) The cells that secrete them (autocrine action),
b) Local cells (paracrine action),
c) Distant cells (endocrine action).
Target cells include: B-, T-, NK-, Th-, Th2-, stem, mast, plasma, progenitor, and tumor cells, and phagocytes, neutrophils, monocytes, and macrophages.
Cytokines bind to specific membrane receptors:
a) Hematopoietin family receptors - dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence. The two subunits are i), cytokine-specific, and ii) signal transducing. Cytokine binding promotes dimerization of the alpha and beta subunits, which then associate with cytoplasmic tyrosine kinases to phosphorylate proteins and activate mRNA transcription. Examples - receptors for IL-2 through IL-7 and GM-CSF.
b) Interferon family receptors have the conserved cysteine residues but not the Trp-Ser-X-Trp-Ser sequence, and include the receptors for IFNa, IFNb, and IFNg.
c) Tumor Necrosis Factor family receptors possess four extracellular domains, and include receptors for soluble TNFa and TNFb as well as membrane-bound CD40 (important for B cell and macrophage activation) and Fas (which signals the cell to undergo apoptosis).
d) Chemokine family receptors have seven transmembrane helices and interact with G protein. This family includes receptors for IL-8, MIP-1 and RANTES. Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.
Cytokines are often produced in cascades, as one cytokine stimulates its target cells to produce additional cytokines. Cytokines are redundant in their activity, in that different cytokines can stimulated similar functions. Different cell types may secrete the same cytokine, or for a single cytokine may act on several different cell types (pleiotropy). Cytokines can also act synergistically with two or more cytokines acting together, or antagonistically with cytokines causing opposing activities.
The largest group of cytokines stimulates proliferation and differentiation of immune cells. The group includes Interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFNg), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate hematopoiesis.
Short half lives, low plasma concentrations, pleiotropy, and redundancy combine to make the isolation and characterization of cytokines difficult. Search for novel cytokines is often conducted at the DNA level, identifying genes that are similar to known cytokine genes.
Tables Immune Cytokines Cell signaling Receptor Tyrosine Kinases(RTK) Second Messengers Phosphate-handling Enzymes Cell Adhesion Molecules (CAM) .
· adenylyl (adenylate) cyclase · cadherins · calcium ions · cAMP-dependent protein kinase · CDKs · chemotaxis · cyclin-dependent kinases · cytokine receptors · DAG · diacylglycerol · DNA ligases · ERKs · GPCRs · GPCR families · guanylate cyclases · guanyl cyclase · Ig superfamily · inositol triphosphate · integrins · IP3 · MAP kinases · mitogen activated protein kinases · phosphatases · phosphodiesterases · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · selectins · signal transduction · TNFs · two-component systems ·
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