title: Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.
abstract: Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40-/-murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Marks
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Naudin
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Nolan
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Goggins
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Burns
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: S W
authors.initials: SW
authors.lastname: Mateer
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: J K
authors.initials: JK
authors.lastname: Latimore
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Minahan
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Plank
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Callister
authors.affiliation: Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.|School of Medicine, Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Veysey
authors.affiliation: Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.|School of Medicine, Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: M M
authors.initials: MM
authors.lastname: Walker
authors.affiliation: Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.|School of Medicine, Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: N J
authors.initials: NJ
authors.lastname: Talley
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, School of Medicine, University of Queensland, Brisbane, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Radford-Smith
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Priority Research Centre for Digestive Health and Neurogastroenterology, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Keely
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053762:Interleukin-12 Subunit p40; D064800:Prolyl-Hydroxylase Inhibitors