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 .
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 , , .
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 , , , , . Also, IL-12 promotes expression of Interferon regulatory factor 1 ( IRF1 ) and 4 ( IRF4 ) in a STAT4 -dependent manner , .
In NK cells, IL-12 induce d cytotoxic events by STAT4 activation of Perforin 1 ( perforin ) gene at its promoter .
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 , , , .
IL-12 has the capacity to induce STAT5 protein. JAK2 activation by IL-12R induces STAT5 phosphorylation thus promoting cellular proliferation . 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 , .
Another negative regulator of IL-12 signaling is Protein inhibitor of activated STAT 2 ( PIAS2 ). It binds to STAT4 and represses its transcriptional activity .
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 , .