Inflammatory bowel disease (IBD) is a group of conditions that are characterised by chronic inflammation of the gastrointestinal tract. During inflammation an oxygen deficit (hypoxia), occurs due to increased metabolic demands created by cellular proliferation and infiltration, coupled with reduced oxygen supply due to vascular damage. Hypoxia activates the transcription factor, hypoxia-inducible factor (HIF), which is capable of regulating the immune response, including cytokine production. The cytokines, IL-12 and IL-23, are pro-inflammatory heterodimeric molecules pivotal to the induction immune response that drives intestinal inflammation. IL-12 consists of heterodimers of IL-12p40 and IL-12p35 subunits, while IL-23 is a heterodimer of the common subunit IL-12p40 and IL-23p19.
We and others have shown that pharmacological stabilisation of HIF, using prolyl hydroxylase inhibitors (PHDi), ameliorates colitis. We hypothesise that this protective effect is due to HIF-mediated transcriptional regulation of the IL-12 family of cytokines. PHDi treatment during DSS-colitis inhibited IFN-γ and IL-17 production from CD4+ T cells in the colonic lamina propria. PHDi treatment was not protective against colitis-induced weight loss and disease activity in IL-12p40-/- mice, and therefore HIF stabilisation resulted in protection against murine DSS colitis in an IL-12p40-dependent manner. These results suggest that HIF may shift the balance of IL-12 signalling from a pro- to anti-inflammatory pathway through regulation of IL-12 and IL-23. The emergence of this pathway is of importance to the progression of chronic inflammation in IBD.