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[Home] [Cytokines] [Description] [Features & Philosophy] [Comparison] |
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[Class I] [Class II] [What is a Chemokine] [Chemokine Receptor Family] |
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The chemokine receptors are members of a superfamily of seven transmembrane loops and transduce their signals through heterotrimeric G proteins. Chemokine receptors are structurally related and can be categorized into specific (bind only one known ligand - e.g., CXCR1/IL8RA and CXCR4/fusin/LESTR), shared (CXCR2/IL8RB, CXCR3, CCCR1-CCCR5), promiscuous (bind to many chemokine ligands of either CXC or CC types - e.g. Duffy blood group antigen), and viral (shared receptors that have been transduced into viral genomes during evolution - herpes saimiri virus and cytomegalovirus). As might be expected, some chemokine receptors are structurally related. For example, CXCR1 and CXCR2 receptors are approximately 65% identical. The N-terminal portion of chemokine receptors is key to determining ligand binding specificity. If engagement of chemokine receptors results in the movement of the cell, a complex series of signaling circuits are involved. Different pathways lead to activation and proliferation. Clearly it is necessary that there be mechanisms by which cytokines are downregulated. Examples include: (1) Cytokine antagonists such as the IL-1 receptor antagonist (IL-1Ra) which binds to the IL-1 receptor. Antagonists bind to a specific receptor but do not transmit a signal. Production of IL-1Ra appears to play a role in regulating the intensity of the inflammatory response. (2) Soluble cytokine receptors can be found in the blood and extracellular fluid. These soluble receptors result from enzymatic cleavage of the extracellular domain of cell-bound cytokine receptors. The released soluble fragments can bind cytokine molecules, thereby neutralizing their activity. The soluble IL-2 receptor (sIL-2R) , which is released following chronic T cell activation is the best characterized. The shed receptor can bind IL-2 and prevent its interaction with the membrane-bound IL-2R. (3) Other cytokines, acting through quite separate receptors, could exert opposite effects on cells. (4) Cytokines could bind to receptors that do not activate the cell. Cytokine antagonists are being considered for use as treatments for diseases associated with overproduction of cytokines - such as bacterial septic shock (gram negative bacteria with overproduction of TNF-a or IL-1) or bacterial toxic shock (bacterial superantigens with overproduction of TNF-a or IL-1). Clinical uses of cytokines: Given the large number of cytokines, it is disappointing that relatively few can be used clinically. Generally, cytokines with more restricted target-cell spectra are more likely to be useful for treatment. Examples include (this is by no means a complete list): Colony stimulating factors (CSFs) - hematological disorders associated with cancer therapy Erythropoietin (EPO) - anemia associated with kidney disease IFN-ß - multiple sclerosis IFN-g - chronic granulomatous disease (GCD) Growth hormone - growth hormone deficiency IL-2 - kidney cancer, melanoma IL-11 - thrombocytopenia following high dose chemotherapy |
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[Home] [Cytokines] [Description] [Features & Philosophy] [Comparison] |
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[Class I] [Class II] [What is a Chemokine] [Chemokine Receptor Family] |
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Pathology Course Menu | Pathology | NJMed P.C. | NJMS | Search | UMDNJ |
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Please direct questions and coments to Alexander G. Izaguirre izaguial@umdnj.edu |
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