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Submitted on December 6, 2004
Accepted on April 18, 2005
Fearing Research Laboratory, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115
* To whom correspondence should be addressed. E-mail: danny.schust{at}bmc.org.
The transcription factor T-bet promotes the differentiation of inflammatory Th1 T helper cells. T-bet expression in lymphoid cells is regulated by cytoplasmic signaling through Janus kinase (JAK) phosphorylation, nuclear signaling utilizing Stat family proteins and autocrine/paracrine feedback involving IFN-gamma. T-bet is here shown to be present in epithelial cells of the human female reproductive tract. Regulation of T-bet expression was modulated by cytokines and the female reproductive steroids, estrogen and progesterone. The mechanisms of T-bet regulation in epithelia differ from those in conventional immune cells. During fifteen days exposure to progesterone, T-bet levels in endometrial epithelial cells (EEC) undulated. Prior exposure to estrogen enhanced these effects. More prolonged exposure of EEC to these hormones singly or in combination, suppressed T-bet production. Stat1 and Stat 5 bound to the EEC T-bet regulatory region (TRR) at the interferon (IFN)-gamma activated sequence (GAS) site, but Stat3 and Stat 4 did not. Binding of Stat1 and Stat 5 to the TRR were modified by progesterone in distinct ways. Estrogen suppressed the binding of Stat1 and Stat 5 to the TRR. Mutation of GAS element reduced T-bet promoter activity, binding of Stat proteins to the TRR and regulation of the promoter by cytokines and hormones. In EEC, cytokine exposure caused phosphorylation of JAK2 and TRR-bound Stat proteins; female steroid hormones altered only phosphorylation of TRR-bound Stat5. While there is no autocrine IFN-gamma feedback loop in reproductive tract epithelial cells, an IL-15/T-bet positive feedback loop may exist. The implications of hormonally regulated T-bet expression are discussed.
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