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.

The triune of intestinal microbiome, genetics and inflammatory status and its impact on the healing of lower gastrointestinal anastomoses

“…As oxygen becomes plentiful, PHDs hydroxylate the inducible α subunit and target it for degradation. So central is the role of HIF1 in maintenance of mucosal homeostasis that inhibitors of PHDs are being trialled clinically as treatment for the chronic inflammatory states of Crohn's disease and ulcerative colitis .…”

Dietary Nondigestible Polysaccharides Ameliorate Colitis by Improving Gut Microbiota and CD4+ Differentiation, as Well as Facilitating M2 Macrophage Polarization

“…Aberrant CD4 + T-cell responses have been ascribed a central role in colitis-associated pathology, and the bowel inflammation in CD is generally associated with increased IFN-γ and IL-17A expression (indicative of Th1 and Th17 cells, respectively). 3,22,36 We demonstrate that MF treatment suppressed Th1 and Th17 cell differentiation in IL-10 −/− mice with colitis. These findings could, at least in part, result in significant improvements in the body weight through increased intestinal absorption.…”

“…The therapeutic effect of MF was further proved by notable decreased colonic MPO concentration, a useful indicator of the extent of neutrophil infiltration, which was in accordance with the histological results. Aberrant CD4 + T‐cell responses have been ascribed a central role in colitis‐associated pathology, and the bowel inflammation in CD is generally associated with increased IFN‐γ and IL‐17A expression (indicative of Th1 and Th17 cells, respectively) . We demonstrate that MF treatment suppressed Th1 and Th17 cell differentiation in IL‐10 −/− mice with colitis.…”

“…Notably, increased concentrations of MPO in IL‐10 −/− mice were reduced by MF treatment (Figure D). It has been shown that chronic inflammation in the colon of IL‐10 −/− mice is mainly mediated by Th1 and Th17 cells . IL‐17A and IFN‐γ levels are elevated in patients with CD, and both are believed to mediate colitis in IL‐10 −/− mice.…”

“…It has been shown that chronic inflammation in the colon of IL-10 −/− mice is mainly mediated by Th1 and Th17 cells. 22 IL-17A and IFN-γ levels are elevated in patients with CD, and both are believed to mediate colitis in IL-10 −/− mice. As expected, significant increased frequency of IL-17A-and IFN-γproducing T cells was observed in IL-10 −/− mice compared with WT mice, and the frequency of Th1/Th17 cells was reduced by MF treatment (Figure 1E).…”