title: 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.
abstract: 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.
authors.affiliation: Fearing Research Laboratory, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kawana
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Schust
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005836:Genitalia, Female / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D053614:Janus Kinase 2; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D011374:Progesterone / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013256:Steroids / Q000378:metabolism*; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D004967:Estrogens; D009841:Oligonucleotides; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013256:Steroids; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D011374:Progesterone; D007371:Interferon-gamma; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2