IL-12 signaling pathway
IL-12 is a key immunoregulatory cytokine that coordinates innate and adaptive immune response. Major event of IL-12 signaling is activation of Signal transducers and activators of transcription (STATs), mainly STAT4, to promote differentiation of native CD4+T cells into T-helper (Th) 1 cells, NK cellular cytotoxicity and T cell proliferation .
The main role of IL-12 is activation of IFN-gamma production. Upon binding to its receptor, IL-12 activates Janus family kinases Tyk2 and JAK2. IL-12RB1 binds the Tyk2, whereas 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 c-Jun to IFN-gamma promoter , , .
Upon IL-12 action, STAT4 also induces transcription of IL-12RB2 and IL-18R1, that leads to amplification of IL-12 signaling and T-helper 1 cell differentiation , , , , . Also, IL-12 promotes expression of IRF1 and IRF4 in a STAT4-dependent manner , .
In addition, IL-12 promotes expression of IL-2R alpha chain by recruiting STAT4 and c-Jun to the promoter of IL-2R alpha chain and thereby enhancing T cell proliferation , .
In NK cells, IL-12 induced cytotoxic events by STAT4 activation of Perforin gene at its promoter .
And lastly, IL-12-induced STAT4 activation leading to expression of G6NT, enzyme responsible for P-selectin ligand formation. This auguments cell adhesion during T cell differentiation , , , .
IL-12 has the capacity to induce STAT5 protein. JAK2 activation by IL-12 receptor induces STAT5 phosphorylation thus promoting cellular proliferation . However, there is evidence that STAT5A can suppress IL-12-induced T-helper 1 cell differentiation through the induction of SOCS3 expression. SOCS3 inhibits IL-12 signaling by binding to the STAT4 docking site of the IL-12RB2 subunit , .
Another negative regulator of IL-12 signaling is PIAS2. It binds to STAT4 and represses its transcriptional activity .
It was shown that STAT4 undergoes proteasomal degradation (see proteasomal protein catabolic process during IL-12 signaling. PDLIM2 was identified as an ubiquitin E3 ligase that acts on STAT4 protein to cause its proteasome-mediated degradation see proteasomal protein catabolic process , .
| G6NT || Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase |
| IFN-gamma || Interferon gamma |
| IL-12 || IL-12 Complex |
| IL-12 receptor || IL-12 receptor Complex |
| IL-12RB1 || Interleukin-12 receptor subunit beta-1 |
| IL-12RB2 || Interleukin-12 receptor subunit beta-2 |
| IL-18R1 || Interleukin-18 receptor 1 |
| IL-2R alpha chain || Interleukin-2 receptor subunit alpha |
| IRF1 || Interferon regulatory factor 1 |
| IRF4 || Interferon regulatory factor 4 |
| JAK2 || Tyrosine-protein kinase JAK2 |
| P-selectin || P-selectin |
| PDLIM2 || PDZ and LIM domain protein 2 |
| PIAS2 || E3 SUMO-protein ligase PIAS2 |
| Perforin || Perforin-1 |
| SOCS3 || Suppressor of cytokine signaling 3 |
| STAT3 || Signal transducer and activator of transcription 3 |
| STAT4 || Signal transducer and activator of transcription 4 |
| STAT5 || Signal transducer and activator of transcription 5 Protein group |
| STAT5A || Signal transducer and activator of transcription 5A |
| Tyk2 || Non-receptor tyrosine-protein kinase TYK2 |
| c-Jun || Transcription factor AP-1 |
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