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

Center for Molecular Medicine and Infectious Diseases (E.K., R.A.P., R.D., C.G., R.M.G., S.A.A.), Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech (Virginia Polytechnic Institute and State University), Blacksburg, Virginia 24061; and Institute of Genes and Transplantation (E.K.), Baskent University, 06490 Ankara, Turkey

Address all correspondence and requests for reprints to: Dr. S. Ansar Ahmed, Professor and Head, Biomedical Sciences and Pathobiology, 1410 Prices Fork Road, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24060-0342. E-mail: ansrahmd{at}vt.edu.

Estrogen, a natural immunomodulatory compound, has been shown to promote the induction of a prototype T helper 1 cytokine, interferon (IFN)-, as well as to up-regulate IFN-mediated proinflammatory molecules (nitric oxide, cyclooxygenase 2, monocyte chemoattractant protein 1). Because IL-12 is a major IFN-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) and a truncated form (STAT4β). Interestingly, we found that estrogen treatment preferentially up-regulates the phosphorylation of STAT4β in splenic lymphoid cells. Time kinetic data showed the differential activation of STAT4β in splenic lymphoid cells from estrogen-treated mice, but not in cells from placebo controls. The activation of STAT4β was mediated by IL-12 and not IFN because deliberate addition or neutralization of IL-12, but not IFN, affected the activation of STAT4β. In contrast to IL-12-induced activation of STAT4β in cells from estrogen-treated mice, STAT4 was not increased, rather it tended to be decreased. In this context, STAT4-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 pSTAT4β to bind to the IFN-activated sites (IFN 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 STAT4β. These novel findings are likely to provide new knowledge with regard to estrogen regulation of inflammation.