Cytokine Network Interactive Pathway


Cytokine Network: Technical Overview

The cytokine family of signaling molecules includes several interleukins, a variety of growth and colony-stimulating factors, ciliary neurotrophic factor, interferons, and several other molecules that exhibit pleiotropic effects on cell differentiation, tissue development and homeostasis. Cytokines mediate communication among cells in the immune system through binding to specific receptors on target cells. Their biological actions vary widely depending upon the type of target tissue involved. They are endowed with anti-proliferative properties and regulate the synthesis of acute phase proteins following tissue injury, trauma, inflammation, and sepsis. The receptors for a large number of cytokines have been cloned and shown to be membrane-spanning glycoproteins with their amino termini in the extracellular space. Unlike receptors for growth factors, cytokine receptors generally lack identifiable catalytic activity. The major diagnostic feature of the ‘cytokine’ receptors is the presence, in the extracellular region of the receptor, of a domain containing multiple cysteine residues and a conserved amino acid motif, WSXWS (Trp-Ser-XTrp- Ser) that functions in the recognition and binding of the ligand.

Most cytokine receptors such as those for IL-3, GM-CSF, and the interferons lack intrinsic kinase activity. They are thought to transmit their regulatory signals primarily by the receptor-associated JAK (Janus kinase) family of tyrosine kinases. Ligand-binding to the receptor leads to JAK activation that phosphorylates cytoplasmic STAT (signal transducer and activator of transcription) proteins. Following phosphorylation on tyrosine residues, STATs are dimerized (resulting from phosphotyrosine - SH2 domain association). This dimerization is accompanied by translocation of STAT to the nucleus that results in DNA binding to specific response elements, and stimulation of gene transcription.

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