Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation

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 indu...

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Bibliographic Details
Published in:Mucosal immunology 2017-09, Vol.10 (5), p.1224-1236
Main Authors: Marks, E, Naudin, C, Nolan, G, Goggins, B J, Burns, G, Mateer, S W, Latimore, J K, Minahan, K, Plank, M, Foster, P S, Callister, R, Veysey, M, Walker, M M, Talley, N J, Radford-Smith, G, Keely, S
Format: Article
Language:English
Subjects:
Animal models
Animals
Cells, Cultured
Colitis
Colitis - immunology
Disease Models, Animal
Gene Expression Regulation
Helper cells
Hydroxylase
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-inducible factor 1a
Inflammation
Inflammation - immunology
Inflammatory bowel disease
Interleukin 1
Interleukin 12
Interleukin-12 Subunit p40 - genetics
Interleukin-12 Subunit p40 - metabolism
Intestinal Mucosa - immunology
Intestine
Lamina propria
Lymphocytes T
Mice
Mice, Knockout
Mucosa
Prolyl-Hydroxylase Inhibitors - therapeutic use
Signal Transduction
Th1 Cells - immunology
Th17 Cells - immunology
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Summary: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.
ISSN:1933-0219
1935-3456
DOI:10.1038/mi.2016.135