title: Macrophage migration inhibitory factor counterregulates dexamethasone-mediated suppression of hypoxia-inducible factor-1 alpha function and differentially influences human CD4+ T cell proliferation under hypoxia.
abstract: Hypoxia, a feature of inflammation and tumors, is a potent inducer of the proinflammatory cytokine macrophage migration inhibitory factor (MIF). In transformed cells, MIF was shown to modulate and to be modulated via the oxygen-sensitive transcription factor hypoxia-inducible factor (HIF)-1. Furthermore, anti-inflammatory glucocorticoids (GCs) were described to regulate MIF action. However, in-depth studies of the interaction between MIF and HIF-1 and GC action in nontransformed primary human CD4(+) T cells under hypoxia are missing. Therefore, we investigated the functional relationship between MIF and HIF and the impact of the GC dexamethasone (DEX) on these key players of inflammation in human CD4(+) T cells. In this article, we show that hypoxia, and specifically HIF-1, is a potent and rapid inducer of MIF expression in primary human CD4(+) T cells, as well as in Jurkat T cells. MIF signaling via CD74, in turn, is essential for hypoxia-mediated HIF-1α expression and HIF-1 target gene induction involving ERK/mammalian target of rapamycin activity complemented by PI3K activation upon mitogen stimulation. Furthermore, MIF signaling enhances T cell proliferation under normoxia but not hypoxia. MIF also counterregulates DEX-mediated suppression of MIF and HIF-1α expression. Based on these data, we suggest that hypoxia significantly affects the expression of HIF-1α in a MIF-dependent manner leading to a positive-feedback loop in primary human CD4(+) T cells, thus influencing the lymphoproliferative response and DEX action via the GC receptor. Therefore, we suggest that HIF and/or MIF could be useful targets to optimize GC therapy when treating inflammation.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité University Hospital, 10117 Berlin, Germany. gaber@drfz.de
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber
authors.forename: Saskia
authors.initials: S
authors.lastname: Schellmann
authors.forename: Kerem B
authors.initials: KB
authors.lastname: Erekul
authors.forename: Monique
authors.initials: M
authors.lastname: Fangradt
authors.forename: Karolina
authors.initials: K
authors.lastname: Tykwinska
authors.forename: Martin
authors.initials: M
authors.lastname: Hahne
authors.forename: Patrick
authors.initials: P
authors.lastname: Maschmeyer
authors.forename: Markus
authors.initials: M
authors.lastname: Wagegg
authors.forename: Cindy
authors.initials: C
authors.lastname: Stahn
authors.forename: Paula
authors.initials: P
authors.lastname: Kolar
authors.forename: René
authors.initials: R
authors.lastname: Dziurla
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D019169:Jurkat Cells; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; D008263:Macrophage Migration-Inhibitory Factors; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human