Female steroid hormones use signal transducers and activators of transcription protein-mediated pathways to modulate the expression of T-bet in epithelial cells: a mechanism for local immune regulation in the human reproductive tract.

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 phosphorylation, nuclear signaling using signal transducers and activators of transcription (Stat) family proteins, and autocrine/paracrine feedback involving interferon (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 a 15-d exposure to progesterone, T-bet levels in endometrial epithelial cells (EECs) undulated. Prior exposure to estrogen enhanced these effects. More prolonged exposure of EECs to these hormones, singly or in combination, suppressed T-bet production. Stat1 and Stat5 bound to the EEC T-bet regulatory region (TRR) at the IFN-gamma-activated sequence site, but Stat3 and Stat4 did not. Binding of Stat1 and Stat5 to the TRR were modified by progesterone in distinct ways. Estrogen suppressed the binding of Stat1 and Stat5 to the TRR. Mutation of gamma-activated sequence element reduced T-bet promoter activity, binding of Stat proteins to the TRR and regulation of the promoter by cytokines and hormones. In EECs, cytokine exposure caused phosphorylation of Janus kinase 2 and TRR-bound Stat proteins; female steroid hormones altered only phosphorylation of TRR-bound Stat5. Although 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.

Duke Scholars

Author Danny J Schust Obstetrics and Gynecology, Reproductive Endocrinology & Infe ...