title: Modulation of T lymphocyte function by the pregnane X receptor.
abstract: The pregnane X receptor (PXR) is a ligand-activated transcription factor regulating genes central to drug and hormone metabolism in the liver. Previous reports indicated that PXR is expressed in PBMC, but the role of PXR in immune cells remains unknown. In this paper, we report increased PXR expression in mouse and human T lymphocytes upon immune activation. Furthermore, pharmacologic activation of PXR inhibits T lymphocyte proliferation and anergizes T lymphocytes by decreasing the expression of CD25 and IFN-gamma and decreasing phosphorylated NF-kappaB and MEK1/2. Although these effects are preceded by an increase of suppressor of cytokine signaling 1, a master switch for IFN-gamma expression, in a PXR-dependent manner, T-bet expression remains unchanged. Conversely, PXR-deficient mice exhibit an exaggerated T lymphocyte proliferation and increased CD25 expression. Furthermore, PXR-deficient lymphocytes produce more IFN-gamma and less of the anti-inflammatory cytokine IL-10. In summary, these results reveal a novel immune-regulatory role of PXR in T lymphocytes and identify suppressor of cytokine signaling 1 as an early signal in PXR-mediated T lymphocyte suppression.
authors.affiliation: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dubrac
authors.forename: Andreas
authors.initials: A
authors.lastname: Elentner
authors.forename: Susanne
authors.initials: S
authors.lastname: Ebner
authors.forename: Jutta
authors.initials: J
authors.lastname: Horejs-Hoeck
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D006131:Growth Inhibitors; D053645:Interleukin-2 Receptor alpha Subunit; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D007371:Interferon-gamma