Pathway Map Details

Immune response_IL-12 signaling pathway

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Object list (links open in MetaCore):

PIAS2, IL-2R alpha chain, Perforin, IFN-gamma, c-Jun, JAK2, STAT3, IL-12RB1, SOCS3, IRF1, Tyk2, IL-12RB2, IRF4, P-selectin, IL-18R1, IL-12 receptor, STAT4, PDLIM2, G6NT, STAT5, Ubiquitin, STAT5A, IL-12


IL-12 signaling pathway

Interleukin-12 ( IL-12 ) is a key immunoregulatory cytokine that coordinates innate and adaptive immune responses. Major event of IL-12 signaling is activation of Signal transducers and activators of transcription ( STAT s), mainly STAT4, to promote differentiation of native CD4+T cells into T-helper (Th) 1 cells, NK cellular cytotoxicity and proliferation of T cells [1].

The main role of IL-12 is activation of Interferon gamma ( IFN-gamma ) production. Upon binding to its receptor, IL-12 activates Janus family kinases Tyrosine kinase 2 ( Tyk2 ) and Janus kinase 2 ( Jak2 ). I nterleukin 12 receptor, beta 1 ( IL-12RBl ) binds the Tyk2, whereas I nterleukin 12 receptor, beta 2 ( IL-12RB2 ) associates with Jak2. Jak2 phosphorylates the tyrosine residues of STAT3 and STAT4. They translocate to the nucleus and bind to the promoter site of IFN-gamma. STAT4 also recruits Jun oncogene ( c-Jun ) to IFN-gamma promoter [2], [3], [4].

Upon IL-12 action, STAT4 also induces transcription of IL-12RB2 and Interleukin 18 receptor 1 ( IL-18RB1 ), that leads to amplification of IL-12 signaling and Th1 cells differentiation [5], [6], [7], [8], [9]. Also, IL-12 promotes expression of Interferon regulatory factor 1 ( IRF1 ) and 4 ( IRF4 ) in a STAT4 -dependent manner [10], [11].

In addition, IL-12 promotes expression of Interleukin 2 receptor, alpha ( IL-2R ) by recruiting STAT4 and c-Jun to the promoter of IL-2R and thereby enhancing T cell proliferation [12], [13].

In NK cells, IL-12 induce d cytotoxic events by STAT4 activation of Perforin 1 ( perforin ) gene at its promoter [14].

And lastly, IL-12 -induce d STAT4 activation leading to expression of GCNT1 glucosaminyl (N-acetyl) transferase 1 core 2 ( G6NT ), enzyme responsible for SELP selectin P (P-selectin ) ligand formation. This augments cell adhesion during T-cell differentiation [15], [16], [17], [18].

IL-12 has the capacity to induce STAT5 protein. JAK2 activation by IL-12R induces STAT5 phosphorylation thus promoting cellular proliferation [19]. However, there is evidence that STAT5A can suppress IL-12 -induced Th1 cell differentiation through the induction of Suppressor of cytokine signaling 3 ( SOCS3 ) expression. SOCS3 inhibits IL-12 signaling by binding to the STAT4 docking site of the IL-12RB2 subunit [20], [21].

Another negative regulator of IL-12 signaling is Protein inhibitor of activated STAT 2 ( PIAS2 ). It binds to STAT4 and represses its transcriptional activity [22].

It was shown that STAT4 undergoes proteosomal degradation during IL-12 signaling. PDZ and LIM domain 2 ( PDLIM2 ) was identified as an ubiquitin E3 ligase that acts on STAT4 protein to cause its proteosome-mediated degradation [23], [24].


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    Direct interaction of major histocompatibility complex class II-derived peptides with class Ia phosphoinositide 3-kinase results in dose-dependent stimulatory effects. The Journal of biological chemistry 2004 Feb 27;279(9):7505-11
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    The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. Biochemical and biophysical research communications 2002 Oct 11;297(5):1245-52
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    Expression of functional selectin ligands on Th cells is differentially regulated by IL-12 and IL-4. Journal of immunology (Baltimore, Md. : 1950) 1999 Mar 15;162(6):3193-201
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    Cutting edge: differential requirements for Stat4 in expression of glycosyltransferases responsible for selectin ligand formation in Th1 cells. Journal of immunology (Baltimore, Md. : 1950) 2001 Jul 15;167(2):628-31
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    Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression. Journal of immunology (Baltimore, Md. : 1950) 2005 Apr 1;174(7):4105-12
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    Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation. Blood 2001 Jun 15;97(12):3860-6
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    SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 2005 Jun;22(6):729-36