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Estrogen, a natural immunomodulatory compound, has been shown to promote the induction of a prototype T helper 1 cytokine, interferon (IFN)-gamma, as well as to up-regulate IFNgamma-mediated proinflammatory molecules (nitric oxide, cyclooxygenase 2, monocyte chemoattractant protein 1). Because IL-12 is a major IFNgamma-inducing cytokine, in this study we investigated whether estrogen treatment of wild-type C57BL/6 mice alters IL-12-mediated signaling pathways. A recent study has shown that IL-12 activates two isoforms of signal transducer and activation of transcription (STAT) 4, a normal-sized (full-length STAT4alpha) and a truncated form (STAT4beta). Interestingly, we found that estrogen treatment preferentially up-regulates the phosphorylation of STAT4beta in splenic lymphoid cells. Time kinetic data showed the differential activation of STAT4beta in splenic lymphoid cells from estrogen-treated mice, but not in cells from placebo controls. The activation of STAT4beta was mediated by IL-12 and not IFNgamma because deliberate addition or neutralization of IL-12, but not IFNgamma, affected the activation of STAT4beta. In contrast to IL-12-induced activation of STAT4beta in cells from estrogen-treated mice, STAT4alpha was not increased, rather it tended to be decreased. In this context, STAT4alpha-induced p27(kip1) protein was decreased in concanavalin A + IL-12-activated lymphocytes from estrogen-treated mice only. By using the in vitro DNA binding assay, we confirmed the ability of pSTAT4beta to bind to the IFNgamma-activated sites (IFNgamma activation sequences)/STAT4-binding sites in estrogen-treated mice. Our data are the first to show that estrogen apparently has selective effects on IL-12-mediated signaling by preferentially activating STAT4beta. These novel findings are likely to provide new knowledge with regard to estrogen regulation of inflammation.

endocrinology

Signal Transducer and Activation of Transcription (STAT) 4β, a Shorter Isoform of Interleukin-12-Induced STAT4, Is Preferentially Activated by Estrogen