A partial agonist for retinoid X receptor mitigates experimental colitis

Onuki Masayoshi, Watanabe Masaki, Ishihara Narumi, Suzuki Koichiro, Takizawa Kei, Hirota Masato, Yamada Takahiro, Egawa Aiko, Shibahara Osamu, Nishii Midori, Fujihara Michiko, Makishima Makoto, Daisuke Takahashi, Furusawa Yukihiro, Kakuta Hiroki, Hase Koji

Research output: Contribution to journalArticle

1 Citation (Scopus)

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(PPARd) 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.

Original languageEnglish
Pages (from-to)251-262
Number of pages12
JournalInternational Immunology
Volume31
Issue number4
DOIs
Publication statusPublished - 2019 Feb 19

Fingerprint

Retinoid X Receptors
Colitis
Cytoplasmic and Nuclear Receptors
Ulcerative Colitis
Peroxisome Proliferator-Activated Receptors
Docosahexaenoic Acids
Cytokines
Inflammatory Bowel Diseases
Crohn Disease
Monocytes
Down-Regulation
Macrophages
Dextran Sulfate
Unsaturated Fatty Acids
Causality
Lipopolysaccharides
Gastrointestinal Tract
Colon
Fats
Diet

Keywords

  • inflammatory bowel disease
  • monocytes
  • Nur77
  • PPARδ
  • RXR

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Masayoshi, O., Masaki, W., Narumi, I., Koichiro, S., Kei, T., Masato, H., ... Koji, H. (2019). A partial agonist for retinoid X receptor mitigates experimental colitis. International Immunology, 31(4), 251-262. https://doi.org/10.1093/intimm/dxy089

A partial agonist for retinoid X receptor mitigates experimental colitis. / Masayoshi, Onuki; Masaki, Watanabe; Narumi, Ishihara; Koichiro, Suzuki; Kei, Takizawa; Masato, Hirota; Takahiro, Yamada; Aiko, Egawa; Osamu, Shibahara; Midori, Nishii; Michiko, Fujihara; Makoto, Makishima; Takahashi, Daisuke; Yukihiro, Furusawa; Hiroki, Kakuta; Koji, Hase.

In: International Immunology, Vol. 31, No. 4, 19.02.2019, p. 251-262.

Research output: Contribution to journalArticle

Masayoshi, O, Masaki, W, Narumi, I, Koichiro, S, Kei, T, Masato, H, Takahiro, Y, Aiko, E, Osamu, S, Midori, N, Michiko, F, Makoto, M, Takahashi, D, Yukihiro, F, Hiroki, K & Koji, H 2019, 'A partial agonist for retinoid X receptor mitigates experimental colitis', International Immunology, vol. 31, no. 4, pp. 251-262. https://doi.org/10.1093/intimm/dxy089
Masayoshi O, Masaki W, Narumi I, Koichiro S, Kei T, Masato H et al. A partial agonist for retinoid X receptor mitigates experimental colitis. International Immunology. 2019 Feb 19;31(4):251-262. https://doi.org/10.1093/intimm/dxy089
Masayoshi, Onuki ; Masaki, Watanabe ; Narumi, Ishihara ; Koichiro, Suzuki ; Kei, Takizawa ; Masato, Hirota ; Takahiro, Yamada ; Aiko, Egawa ; Osamu, Shibahara ; Midori, Nishii ; Michiko, Fujihara ; Makoto, Makishima ; Takahashi, Daisuke ; Yukihiro, Furusawa ; Hiroki, Kakuta ; Koji, Hase. / A partial agonist for retinoid X receptor mitigates experimental colitis. In: International Immunology. 2019 ; Vol. 31, No. 4. pp. 251-262.
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AU - Midori, Nishii

AU - Michiko, Fujihara

AU - Makoto, Makishima

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AU - Hiroki, Kakuta

AU - Koji, Hase

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