Hydroxylases as therapeutic targets in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a common and debilitating clinical disorder comprising ulcerative colitis and Crohn's disease. IBD occurs when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material. This in turn results in the cycles of inflammation and further barrier dysfunction which underlie disease progression. Although significant therapeutic advances have been made over the last decade, current immunosuppressive and anti-inflammatory treatments for IBD have significant limitations due to lack of treatment response in some patients and adverse effects, including increased risk of infection and malignancy. Recent studies using experimental models of IBD have identified that intracellular hydroxylases, a group of enzymes responsible for oxygen sensing and activation of adaptive transcriptional responses to hypoxia may represent a new class of therapeutic targets in IBD. Hydroxylase inhibitors are effective in ameliorating symptoms of colitis at least in part through the promotion of intestinal epithelial barrier function. The mechanism of this protection is due to activation of hypoxia-sensitive transcription factors, including the hypoxiainducible factor (HIF) and nuclear factor kappa-B (NF-kB), which activate specific epithelial barrier-protective transcriptional programs. In this review, the mechanism(s) of action and the therapeutic potential of small molecule hydroxylase inhibitors for the treatment of IBD will be discussed.

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…However, given the complex and pleiotropic roles of hypoxia-responsive pathways in distinct immune cell types, a prediction of whether hypoxia and/or hydroxylase inhibition would ultimately be pro-or antiinflammatory is difficult to make without testing the impact of pharmacological hydroxylase inhibition in vivo. Studies implicating hypoxia-responsive pathways in inflammatory disease are supported by data demonstrating the impact of targeting the HIF pathway with pharmacological hydroxylase inhibitors for the treatment of inflammatory disease (12,103). Initial work in this area demonstrated a beneficial effect of hydroxylase inhibition on disease progression in mouse models of colitis (104,105).…”

Regulation of IL-1β–induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways

“…However, the net effect of pharmacologic activation of this pathway through inhibition of hydroxylases in vivo is anti-inflammatory. The complex role of HIF and inflammation and its potential as a therapeutic target have been recently reviewed (1)(2)(3)7).…”

Nitric Oxide Interferes With Hypoxia Signaling During Colonic Inflammation

“…T-cells that infiltrated the inflamed mucosa in IBD patients expressed more HIF-1a, and HIF-1a KO mice displayed more severe DSS-induced colonic inflammation (12) . Based on these positive reports, PHD inhibitors have been suggested for use as a potential therapeutic approach to treat IBD patients (7) . However, infliximab (an anti-TNF-a therapy) has demonstrated positive results by inhibiting angiogenic processes through VEGF-A inhibition in IBD patients (22) .…”