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 [1].

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 [2], [3], [4].

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 [5], [6], [7], [8], [9]. Also, IL-12 promotes expression of IRF1 and IRF4 in a STAT4-dependent manner [10], [11].

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 [12], [13].

In NK cells, IL-12 induced cytotoxic events by STAT4 activation of Perforin gene at its promoter [14].

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 [15], [16], [17], [18].

IL-12 has the capacity to induce STAT5 protein. JAK2 activation by IL-12 receptor induces STAT5 phosphorylation thus promoting cellular proliferation [19]. 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 [20], [21].

Another negative regulator of IL-12 signaling is PIAS2. It binds to STAT4 and represses its transcriptional activity [22].

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 [23], [24].

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