17beta-estradiol downregulates interferon regulatory factor-1 in murine splenocytes

Interferon regulatory factor-1 (IRF-1) is an important transcription factor that mediates interferon-gamma (IFN-gamma)-induced cell-signaling events. In this study, we examined whether 17beta-estradiol alters IRF-1 in splenic lymphocytes, in view of the immunomodulatory effects of this natural female sex hormone including its ability to alter IFN-gamma levels. We find that IRF-1 expression is markedly downregulated in splenocytes or purified T-cells from estrogen-treated mice at all time points studied when compared with their placebo counterparts. This decrease in IRF-1 in splenocytes from estrogen-treated mice is neither due to upregulation of IRF-1-interfering proteins (nucleophosmin or signal transducer and activator of transcription (STAT)-5) nor due to alternatively spliced IRF-1 mRNA. Given that IFN-gamma is a potent inducer of IRF-1, direct addition of recombinant IFN-gamma to splenocytes from either wild-type or IFN-gamma-knockout mice, or the addition of recombinant IFN-gamma to purified T-cells, was expected to stimulate IRF-1 expression. However, robust expression of IRF-1 in cells from estrogen-treated mice was not seen, unlike what was observed in cells from placebo-treated mice. Diminished IFN-gamma induction of IRF-1 in cells from estrogen-treated mice was noticed despite comparable phosphorylated STAT-1 activation. These studies are the first to show that estrogen regulates IFN-gamma-inducible IRF-1 in lymphoid cells, a finding that may have implications to IFN-gamma-regulated immune and vascular diseases.