Malt1 inactivation attenuates experimental colitis through the regulation of Th17 and Th1/17 cells
- 107 Downloads
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.
Effects of Malt1 protease on the activation of T cells and the development of experimental colitis was investigated using Malt1 protease-deficient (PD) mouse.
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.
Inactivation of Malt1 protease activity abrogates Th17 and Th1/17 cell activation, resulting in the amelioration of experimental colitis.
KeywordsMalt1 Experimental colitis Th17 cells Th1/17 cells IL-17
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147(3):618 – 27.e3. https://doi.org/10.1053/j.gastro.2014.05.008.CrossRefGoogle Scholar
- 5.Peyrin-Biroulet L, Danese S, Argollo M, Pouillon L, Peppas S, Gonzalez-Lorenzo M, et al. Loss of response to vedolizumab and ability of dose intensification to restore response in patients with Crohn’s disease or ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2018. https://doi.org/10.1016/j.cgh.2018.06.026.Google Scholar
- 7.Feagan BG, Sandborn WJ, D’Haens G, Panes J, Kaser A, Ferrante M, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389(10080):1699–709. https://doi.org/10.1016/s0140-6736(17)30570-6.CrossRefGoogle Scholar
- 11.Globig AM, Hennecke N, Martin B, Seidl M, Ruf G, Hasselblatt P, et al. Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-gamma+ IL-17+ coproducing CD4+ T cells in active inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(12):2321–9. https://doi.org/10.1097/mib.0000000000000210.CrossRefGoogle Scholar
- 25.Uo M, Hisamatsu T, Miyoshi J, Kaito D, Yoneno K, Kitazume MT, et al. Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcgammaR-mediated CD14 macrophage activation. Gut. 2013;62(12):1734–44. https://doi.org/10.1136/gutjnl-2012-303063.CrossRefGoogle Scholar