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Malt1 inactivation attenuates experimental colitis through the regulation of Th17 and Th1/17 cells

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Abstract

Objective and design

Protease activity of MALT lymphoma-translocation protein 1 (Malt1) plays an important role in the development of colitis, but the detailed mechanism has not been fully elucidated.

Method

Effects of Malt1 protease on the activation of T cells and the development of experimental colitis was investigated using Malt1 protease-deficient (PD) mouse.

Results

IL-2 production from CD4+ T cells of Malt1 PD mice was decreased compared with that of wild-type (WT) mice. Intraperitoneal injection of anti-CD3 antibody into Malt1 PD mouse induced less productions of IL-17 in the plasma, as well as the colonic gene expression of IL-17A, compared with WT mice, whereas IFN-γ production was not impaired. In naïve T-cell transfer colitis model, Malt1 PD T cells induced less disease severity than WT T cells. Then, reduction in the populations of Th17 and Th1/17 cells was observed in the mesenteric lymph nodes of the recipient mice transferred with Malt1 PD T cells, whereas those of Th1 cells were not impaired. IL-17A expression in the colon was also decreased in the mouse receiving Malt1 PD T cells.

Conclusions

Inactivation of Malt1 protease activity abrogates Th17 and Th1/17 cell activation, resulting in the amelioration of experimental colitis.

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Acknowledgements

We thank the following employees of Takeda Pharmaceutical Company Limited, Naoko Matsunaga and Takeo Arita, for contributing to discussion on in vivo experiment, Hikaru Saito for contributing to in vivo experiment, and Kimihiko Iwachidow, Takashi Yano, and Yuki Nakamura for contributing to generation, breeding and supply of Malt1 PD mouse.

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Author notes

  1. Yoshiki Nakamura

    Present address: Pharmaceutical Sciences, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

  2. Keiko Igaki

    Present address: Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

Authors and Affiliations

  1. Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan

    Yoshiki Nakamura, Keiko Igaki, Yusaku Komoike, Kazumasa Yokoyama & Noboru Tsuchimori

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  1. Yoshiki Nakamura
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Correspondence to Noboru Tsuchimori.

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Nakamura, Y., Igaki, K., Komoike, Y. et al. Malt1 inactivation attenuates experimental colitis through the regulation of Th17 and Th1/17 cells. Inflamm. Res. 68, 223–230 (2019). https://doi.org/10.1007/s00011-018-1207-y

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  • DOI: https://doi.org/10.1007/s00011-018-1207-y

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