Immune response IL-12 signaling pathway
IL-12 signaling pathway
Interleukin-12 ( IL-12 ) is a key immunoregulatory cytokine that coordinatesinnate and adaptive immune responses. Major event of IL-12 signaling is activationof Signal transducers and activators of transcription ( STAT s), mainlySTAT4, to promote differentiation of native CD4+T cells into T-helper (Th) 1cells, 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 kinasesTyrosine kinase 2 ( Tyk2 ) and Janus kinase 2 ( Jak2 ). I nterleukin 12receptor, beta 1 ( IL-12RBl ) binds the Tyk2, whereas I nterleukin 12receptor, beta 2 ( IL-12RB2 ) associates with Jak2. Jak2phosphorylates the tyrosine residues of STAT3 and STAT4. They translocateto the nucleus and bind to the promoter site of IFN-gamma. STAT4 also recruits Junoncogene ( c-Jun ) to IFN-gamma promoter [2], [3],[4].
Upon IL-12 action, STAT4 also induces transcription of IL-12RB2and Interleukin 18 receptor 1 ( IL-18RB1 ), that leads to amplification ofIL-12 signaling and Th1 cells differentiation [5], [6],[7], [8], [9]. Also, IL-12 promotesexpression of Interferon regulatory factor 1 ( IRF1 ) and 4 ( IRF4 ) in aSTAT4 -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 ofIL-2R and thereby enhancing T cell proliferation [12], [13].
In NK cells, IL-12 induce d cytotoxic events by STAT4 activation ofPerforin 1 ( perforin ) gene at its promoter [14].
And lastly, IL-12 -induce d STAT4 activation leading to expression ofGCNT1 glucosaminyl (N-acetyl) transferase 1 core 2 ( G6NT ), enzyme responsiblefor SELP selectin P (P-selectin ) ligand formation. This augments cell adhesionduring T-cell differentiation [15], [16], [17],[18].
IL-12 has the capacity to induce STAT5 protein. JAK2 activationby IL-12R induces STAT5 phosphorylation thus promoting cellularproliferation [19]. However, there is evidence that STAT5A can suppressIL-12 -induced Th1 cell differentiation through the induction of Suppressor ofcytokine signaling 3 ( SOCS3 ) expression. SOCS3 inhibits IL-12signaling 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 activatedSTAT 2 ( PIAS2 ). It binds to STAT4 and represses its transcriptionalactivity [22].
It was shown that STAT4 undergoes proteosomal degradation during IL-12signaling. PDZ and LIM domain 2 ( PDLIM2 ) was identified as an ubiquitin E3ligase that acts on STAT4 protein to cause its proteosome-mediated degradation[23], [24].
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