Interleukin-12 family signaling

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Homo sapiens
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Interleukin-12 (IL-12) is a heterodimer of interleukin-12 subunit alpha (IL12A, IL-12p35) and interleukin-12 subunit beta (IL12B, IL-12p40). It is a potent immunoregulatory cytokine involved in the generation of cell mediated immunity to intracellular pathogens. It is produced by antigen presenting cells, including dendritic cells, macrophages/monocytes, neutrophils and some B cells (D'Andrea et al. 1992, Kobayashi et al.1989, Heufler et al.1996). It enhances the cytotoxic activity of natural killer (NK) cells and cytotoxic T cells, stimulating proliferation of activated NK and T cells and induces production of interferon gamma (IFN gamma) by these cells (Stern et al. 1990). IL-12 also plays an important role in immunomodulation by promoting cell mediated immunity through induction of a class 1 T helper cell (Th1) immune response. IL-12 may contribute to immunopathological conditions such as rheumatoid arthritis (McIntyre et al. 1996). The receptor for IL-12 is a heterodimer of IL-12Rbeta1 (IL12RB1) and IL-12Rbeta2 (IL12RB2), both highly homologous to Interleukin-6 receptor subunit beta (IL6ST,gp130). Each has an extracellular ligand binding domain, a transmembrane domain and a cytosolic domain containing box 1 and box 2 sequences that mediate binding of Janus family tyrosine kinases (JAKs). IL-12 binding is believed to bring about the heterodimerization and generation of a high affinity receptor complex capable of signal transduction. In this model, receptor dimerization leads to juxtaposition of the cytosolic domains and subsequent tyrosine phosphorylation and activation of JAK2 and TYK2. These activated kinases, in turn, tyrosine phosphorylate and activate several members of the signal transducer and activator of transcription (STAT) family, mainly STAT4, while also STAT1, STAT3 and STAT5 have been reported to be activated (Bacon et al. 1995, Jacobson et al. 1995, Yu et al. 1996, Gollob et al.1995). The STATs translocate to the nucleus to activate transcription of several genes, including IFN gamma. The production of IFN gamma has a pleiotropic effect in the cell, stimulating production of molecules important to cell mediated immunity. In particular, IFN gamma stimulates production of more IL-12 and sets up a positive regulation loop between IL-12 signaling and IFN gamma (Chan et al. 1991). The importance of IL-12 for this loop is demonstrated by IL-12 and STAT4 knockout mice that are severely compromised in IFN-gamma production (Kaplan et al. 1996; Magram et al. 1996), as well as by patients with IL12B mutations that are severely compromised in IFN-gamma production (Altare et al.1998).

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