title: Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function.
abstract: Tissue hypoxia can occur in physiological and pathological conditions. When O2 availability decreases, the transcription factor hypoxia-inducible factor (HIF)-1α is stabilized and regulates cellular adaptation to hypoxia. The objective of this study was to test whether HIF-1α regulates T cell fate and to define the molecular mechanisms of this control. Our data demonstrate that Th1 cells lose their capacity to produce IFN-γ when cultured under hypoxia. HIF-1α(-/-) Th1 cells were insensitive to hypoxia, underlining a critical role for HIF-1α. Our results point to a role for IL-10, as suggested by the increased IL-10 expression at low O2 levels and the unchanged IFN-γ production by IL-10-deficient Th1 cells stimulated in hypoxic conditions. Accordingly, STAT3 phosphorylation is increased in Th1 cells under hypoxia, leading to enhanced HIF-1α transcription, which, in turn, may inhibit suppressor of cytokine signaling 3 transcription. This positive-feedback loop reinforces STAT3 activation and downregulates Th1 responses that may cause collateral damage to the host.
authors.affiliation: Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
authors.forename: Hussein
authors.initials: H
authors.lastname: Shehade
authors.affiliation: Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Acolty
authors.affiliation: Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Moser
authors.affiliation: Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium guillaume.oldenhove@ulb.ac.be.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Oldenhove
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D056747:Immunomodulation; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D007371:Interferon-gamma