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

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. and Keely, S. (2017) Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation. Mucosal Immunology, 10 5: 1224-1236. doi:10.1038/mi.2016.135

Author 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.
Title Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation
Journal name Mucosal Immunology   Check publisher's open access policy
ISSN 1933-0219
Publication date 2017-09-01
Sub-type Article (original research)
DOI 10.1038/mi.2016.135
Open Access Status Not yet assessed
Volume 10
Issue 5
Start page 1224
End page 1236
Total pages 13
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Subject 2723 Immunology and Allergy
2403 Immunology
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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1021582
Institutional Status UQ

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Sub-type: Article (original research)
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