1. Academic Validation
  2. TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

  • Sci Rep. 2020 Jan 20;10(1):734. doi: 10.1038/s41598-020-57550-5.
Hidehiko Fukushima 1 Yohei Iwata 1 Soichiro Watanabe 1 Kenta Saito 1 Yoshihito Tanaka 1 Yurie Hasegawa 1 Masashi Akiyama 2 Kazumitsu Sugiura 3
Affiliations

Affiliations

  • 1 Department of Dermatology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
  • 2 Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
  • 3 Department of Dermatology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. ksugiura@fujita-hu.ac.jp.
Abstract

Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36RA) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn-/- mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a Toll-like Receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn-/- mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn-/- mice. These data indicate that Il36rn-/- mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response.

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