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

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dc.contributor.authorKarpuzoglu, Ebruen
dc.contributor.authorPhillips, Rebecca A.en
dc.contributor.authorDai, Rujuanen
dc.contributor.authorGraniello, Carmineen
dc.contributor.authorGogal, Robert M.en
dc.contributor.authorAhmed, Sattar Ansaren
dc.date.accessed2014-07-07en
dc.date.accessioned2014-07-08T13:02:17Zen
dc.date.available2014-07-08T13:02:17Zen
dc.date.issued2009-03en
dc.description.abstractEstrogen, 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)en
dc.description.sponsorshipNational Institutes of Health 5RO1 AI51880-03en
dc.description.sponsorshipUnited States Department of Agriculture-Hatchen
dc.description.sponsorshipUnited States Department of Agriculture-Animal Health and Diseaseen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationEbru 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.2008-0832en
dc.identifier.doihttps://doi.org/10.1210/en.2008-0832en
dc.identifier.issn0013-7227en
dc.identifier.urihttp://hdl.handle.net/10919/49392en
dc.identifier.urlhttp://press.endocrine.org/doi/abs/10.1210/en.2008-0832en
dc.language.isoenen
dc.publisherEndocrine Societyen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectsystemic-lupus-erythematosusen
dc.subjectinterferon-gamma productionen
dc.subjectmessenger-rnaen
dc.subjectexpressionen
dc.subjectifn-gammaen
dc.subjectautoimmune-diseasesen
dc.subjectt-cellsen
dc.subjectmurine splenocytesen
dc.subjectgender differencesen
dc.subjectimmune-responsesen
dc.subjectil-12 responsesen
dc.subjectendocrinology & metabolismen
dc.titleSignal Transducer and Activation of Transcription (STAT) 4 beta, a Shorter Isoform of Interleukin-12-Induced STAT4, Is Preferentially Activated by Estrogenen
dc.title.serialEndocrinologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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