Karpuzoglu, EbruPhillips, Rebecca A.Dai, RujuanGraniello, CarmineGogal, Robert M.Ahmed, Sattar Ansar2014-07-082014-07-082009-03Ebru Karpuzoglu, Rebecca A. Phillips, Rujuan Dai, Carmine Graniello, Robert M. Gogal, Jr., and S. Ansar Ahmed. "Signal Transducer and Activation of Transcription (STAT) 4β, a Shorter Isoform of Interleukin-12-Induced STAT4, Is Preferentially Activated by Estrogen," Endocrinology 2009 150:3, 1310-1320. DOI: http://dx.doi.org/10.1210/en.2008-08320013-7227http://hdl.handle.net/10919/49392Estrogen, 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 IFN gamma-mediated pro-inflammatory molecules (nitric oxide, cyclooxygenase 2, monocyte chemoattractant protein 1). Because IL-12 is a major IFN gamma-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 STAT4 alpha) and a truncated form (STAT4 beta). Interestingly, we found that estrogen treatment preferentially up-regulates the phosphorylation of STAT4 beta in splenic lymphoid cells. Time kinetic data showed the differential activation of STAT4 beta in splenic lymphoid cells from estrogen-treated mice, but not in cells from placebo controls. The activation of STAT4 beta was mediated by IL-12 and not IFN gamma because deliberate addition or neutralization of IL-12, but not IFN gamma, affected the activation of STAT4 beta. In contrast to IL-12-induced activation of STAT4 beta in cells from estrogen-treated mice, STAT4 beta was not increased, rather it tended to be decreased. In this context, STAT4 alpha-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 pSTAT4 beta to bind to the IFN gamma-activated sites (IFN gamma 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 STAT4 beta. These novel findings are likely to provide new knowledge with regard to estrogen regulation of inflammation. (Endocrinology 150: 1310-1320, 2009)application/pdfenIn Copyrightsystemic-lupus-erythematosusinterferon-gamma productionmessenger-rnaexpressionifn-gammaautoimmune-diseasest-cellsmurine splenocytesgender differencesimmune-responsesil-12 responsesendocrinology & metabolismArticle - Refereedhttp://press.endocrine.org/doi/abs/10.1210/en.2008-0832https://doi.org/10.1210/en.2008-0832