Role of interleukin-12 induced stat factors in interferon-y gene induction

lnterleukin-12 (IL-12) has pleiotropic effects on responsive cell populations, including enhancement of proliferation, cytolysis and differentation. IL-12 initiates the development of naive helper T cells toward the T helper 1 (Th1 ) pole of phenotype and induces Interferon-4 (IFNy) transcription. We have previously demonstrated that StatS and Stat4 are rapidly tyrosine phosphorylated following IL-12 stimulation of Th1 cells. To test whether these IL-12 induced STATs act directly on the proximal promoter region of the IFNy gene, we performed reporter assays in IL-12 treated cells using the IFNy promoter region which we and others have shown contains most of the antigen-inducible activity. IL-12 did not activate these promoter constructs. |n addition, oligonucleotides derived from this region did not inhibit STAT factor binding when used as competitors in a gel shift assay. However, the time course of IFNy mRNA induction by IL-12 as well as its sensitivity to pharmacologie inhibitors suggests that IL-12 may act directly on this locus, perhaps outside the region tested. We are currently investigating whether IL-12 induced STAT factors may act at a distance to induce IFNy transcription. Support : NIH.