A partial agonist for retinoid X receptor mitigates experimental colitis

Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.

Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases

“…As a result, synergistic activation of the RXR/PPARg heterodimer was established by the PPARg agonists rosiglitazone or troglitazone and the RXR agonist retinoid, suggesting protective combined effects against colon inflammation (Desreumaux et al, 2001). Further, a recent study of DSS-induced colitis showed that the partial RXR agonist CBt-PMN was also capable of ameliorating intestinal inflammation in this mouse model of UC through both PPARb/ d/RXR and Nur77/RXR heterodimer activation (Onuki et al, 2019).…”

Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD

“…Conventional full RXR agonists are known to show considerable adverse effects, but the partial RXR agonist, CBt-PMN, efficiently ameliorated the symptoms of colitis. This effect is attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes probably by the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN (202).…”

ω3 fatty acid metabolite, 12‐hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α

“…For example, it has been reported that the RXR/PPARα axis inhibits NF-κB transcription activity, and the RXR/PPARβ axis suppresses inflammatory interleukin-6 production. 74,75 Agonist-activated RXR/PPAR complexes negatively regulate other transcription factors including NF-κB and activator protein-1, which are involved in the promotion of CXCL1 and CXCL2 expression, thereby inhibiting its ability to induce gene transcription. 66,[75][76][77][78] For the remaining RXR heterodimer, RXR/LXR, an RXR agonist reduced translocation of NF-κB into nuclei F I G U R E 7 Essential role of retinoid X receptor (RXR)α on 12-hydroxyeicosapentaenoic acid (HEPE)-mediated chemokine suppression in keratinocytes.…”