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Anti-inflammatory Effects of Carbon Monoxide-Releasing Molecule on Trinitrobenzene Sulfonic Acid-Induced Colitis in Mice

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Abstract

Background and Aim

Recent findings indicate that carbon monoxide (CO) in non-toxic doses exerts a beneficial anti-inflammatory action in various experimental models. However, the precise anti-inflammatory mechanism of CO in the intestine remains unclear. Here, we assessed the effects of a novel water-soluble CO-releasing molecule, CORM-3, on trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice.

Methods

To induce colitis, C57BL/6 male mice received an enema of TNBS. CORM-3 or its inactive compound, iCORM-3, were administered intraperitoneally, once immediately before, and twice daily after receiving an enema of TNBS. Three days after TNBS administration, the distal colon was removed, assessed for colonic damage and histological scores, polymorphonuclear leukocyte recruitment (tissue-associated myeloperoxidase, MPO activity), and TNF-α, IFN-γ and IL-17A expression (mRNA and protein levels in the colon mucosa). CD4+ T cells isolated from murine spleens were stimulated with anti-CD3/CD28, in the presence or absence of CORM-3/iCORM-3. The cell supernatants were assessed for TNF-α and IFN-γ expression, 24 h following stimulation.

Results

Colonic damage and histological scores were significantly increased in TNBS-induced mice compared to sham-operated mice. Tissue-associated MPO activity and expression of TNF-α, IFN-γ, and IL-17A in the colonic mucosa were higher in TNBS-induced colitis mice. The above changes were attenuated in CORM-3-treated mice. Further, CORM-3 was effective in reducing TNF-α and IFN-γ production in anti-CD3/CD28-stimulated CD4+ T cells.

Conclusions

These findings indicate that CO released from CORM-3 ameliorates inflammatory responses in the colon of TNBS-challenged mice at least in part through a mechanism that involves the suppression of inflammatory cell recruitment/activation.

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Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research (C) to Y.N. (No. 25460958) and (C) to T.T. (No. 25460959) from the Japan Society for the Promotion of Science, and by an Adaptable and Seamless Technology Transfer Program through target driven R&D to Y.N. from the Japan Science and Technology Agency. Dr. Koichiro Yasui evaluated the quality and integrity of the data.

Conflict of interest

Y.I. and N.Y. have an affiliation with a donation-funded department from AstraZeneca CO., Ltd., Eisai CO., Ltd., Otsuka Pharmaceutical Co., Ltd., MSD K.K., Dainippon Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., FUJIFILM Medical Co., Ltd. and Merck Serono Co., Ltd. Y.N. received scholarship funds from Otsuka Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd. Y.I. received scholarship funds from MSD K.K. and Bristol-Myers K.K. The other authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Wataru Fukuda, Tomohisa Takagi, Kazuhiro Katada, Katsura Mizushima, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Kamada, Kazuhiko Uchiyama, Takeshi Ishikawa, Osamu Handa, Hideyuki Konishi, Nobuaki Yagi, Toshikazu Yoshikawa, Yuji Naito & Yoshito Itoh

  2. Department of Medical Life System, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tataramiyakodani Kyotanabe, Kyoto, 610-0394, Japan

    Hiroshi Ichikawa

  3. Centre for Critical Illness Research, Lawson Health Research Institute, 800 Commissioners Rd. E, London, ON, N6A 4G4, Canada

    Gediminas Cepinskas

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  1. Wataru Fukuda
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  2. Tomohisa Takagi
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  3. Kazuhiro Katada
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Correspondence to Tomohisa Takagi.

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Fukuda, W., Takagi, T., Katada, K. et al. Anti-inflammatory Effects of Carbon Monoxide-Releasing Molecule on Trinitrobenzene Sulfonic Acid-Induced Colitis in Mice. Dig Dis Sci 59, 1142–1151 (2014). https://doi.org/10.1007/s10620-013-3014-1

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