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A partial agonist for retinoid X receptor mitigates experimental colitis
- Source :
- International immunology. 31(4)
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Agonist
Lipopolysaccharides
Male
Nerve growth factor IB
Docosahexaenoic Acids
Tetrahydronaphthalenes
medicine.drug_class
Immunology
Retinoid X receptor
Pharmacology
Inflammatory bowel disease
Partial agonist
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Nuclear Receptor Subfamily 4, Group A, Member 1
Immunology and Allergy
Animals
Humans
PPAR delta
Colitis
Receptor
Cells, Cultured
business.industry
Macrophages
Dextran Sulfate
General Medicine
Triazoles
medicine.disease
Inflammatory Bowel Diseases
Ulcerative colitis
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Retinoid X Receptors
Cytokines
Inflammation Mediators
business
030215 immunology
Protein Binding
Subjects
Details
- ISSN :
- 14602377
- Volume :
- 31
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- International immunology
- Accession number :
- edsair.doi.dedup.....07e15ce483726c1bf2bd066af9d136e2