Reduced small-intestinal injury induced by indomethacin in interleukin-17A-deficient mice

Authors

  • Shinya Yamada,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Yuji Naito,

    Corresponding author
    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
      Dr Yuji Naito, Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo-ku, Kyoto 602-8566, Japan. Email: ynaito@koto.kpu-m.ac.jp
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  • Tomohisa Takagi,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Katsura Mizushima,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Yasuko Hirai,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Ryusuke Horie,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Kohei Fukumoto,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Ken Inoue,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Akihito Harusato,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Naohisa Yoshida,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Kazuhiko Uchiyama,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Osamu Handa,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Takeshi Ishikawa,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Hideyuki Konishi,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Naoki Wakabayashi,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Nobuaki Yagi,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Satoshi Kokura,

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Masakazu Kita,

    1. Department of Microbiology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Toshikazu Yoshikawa

    1. Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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  • Conflict of interests: There are no financial/commercial conflicts of interests.

Dr Yuji Naito, Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo-ku, Kyoto 602-8566, Japan. Email: ynaito@koto.kpu-m.ac.jp

Abstract

Background and Aims:  The pathogenesis of enteropathy induced by non-steroidal anti-inflammatory drugs (NSAIDs) is still unclear, and there are no established treatments. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has been associated with the development of chronic inflammatory diseases, including autoimmune diseases. To define the role of IL-17A in small intestinal injury and inflammation, we studied the effects of indomethacin administration in mice with targeted deletions of the IL-17A gene.

Methods:  Male C57BL/6 (wild-type) and homozygous IL-17A-/- C57BL/6 mice were subjected to this study. Indomethacin (10 mg/kg) was subcutaneously administered to induce small-intestinal damage. Indomethacin-induced lesions in the small intestine were evaluated by measuring the injured area and by histopathology. Also assessed were myeloperoxidase (MPO) activity, as an index of neutrophil accumulation, and intestinal mRNA expression for inflammatory cytokines.

Results:  The area of macroscopic ulcerative lesions, the MPO activity and the mRNA expression of inflammatory-associated chemokines, such as keratinocyte chemoattractant (KC), monocyte chemotactic protein-1 (MCP-1), and granulocyte-colony stimulating factor (G-CSF), were significantly increased in indomethacin-treated groups compared with the sham groups. The development of intestinal lesions by indomethacin was inhibited in IL-17A-/- mice compared with wild-type mice, together with significant suppression of the increased levels of MPO activities and KC, MCP-1, and G-CSF levels.

Conclusion:  These findings demonstrate that IL-17A contributes to the development of indomethacin-induced small intestinal injury through upregulation of G-CSF, KC, and MCP-1. IL-17A might be a promising new therapeutic target to treat NSAID-induced enteritis.

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