This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karpuzoglu, E. Articles by Ahmed, S. A. Search for Related Content PubMed PubMed Citation Articles by Karpuzoglu, E. Articles by Ahmed, S. A.

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.

This article has been cited by other articles:

				R. Dai, R. A. Phillips, E. Karpuzoglu, D. Khan, and S. A. Ahmed Estrogen Regulates Transcription Factors STAT-1 and NF-{kappa}B to Promote Inducible Nitric Oxide Synthase and Inflammatory Responses J. Immunol., December 1, 2009; 183(11): 6998 - 7005. [Abstract] [Full Text] [PDF]