MALT1 inhibitors prevent the development of DSS-induced experimental colitis in mice via inhibiting NF-κB and NLRP3 inflammasome activation

Apr 23, 2016Oncotarget

MALT1 blockers may stop experimental colon inflammation in mice by reducing key immune system activations

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Treatment with MALT1 inhibitors MI-2 and mepazine significantly reduced disease symptoms in a mouse model of colitis.

Dose-dependent administration of MI-2 and mepazine led to a decrease in the disease activity index and colon length in mice with experimental colitis.
Histopathological improvements were observed following treatment with MALT1 inhibitors.
MALT1 inhibitors suppressed protein and mRNA levels of proinflammatory cytokines, including TNF, IL-1β, IL-6, IL-18, IL-17A, and IFN-γ in the colon.
The protective effects of MALT1 inhibitors may be linked to their ability to inhibit NF-κB and NLRP3 inflammasome activation in macrophages.
In vitro studies indicated that MALT1 inhibitors reduced the production of IL-1β and IL-18 in specific cell types by suppressing NF-κB and NLRP3 activation.

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Mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), a paracaspase and essential regulator for nuclear factor kB (NF-κB) activation, plays an important role in innate and adaptive immunity. Suppression of MALT1 protease activity with small molecule inhibitors showed promising efficacies in subtypes of B cell lymphoma and improvement in experimental autoimmune encephalomyelitis model. However, whether MALT1 inhibitors could ameliorate colitis remains unclear. In the present study, we examined the pharmacological effect of two specific MALT1 inhibitors MI-2 and mepazine on the dextran sulfate sodium (DSS)-induced experimental colitis in mice, followed by mechanistic analysis on NF-κB and NLRP3 inflammasome activation. Treatment with MI-2 and mepazine dose-dependently attenuated symptoms of colitis in mice, evidenced by reduction in the elevated disease activity index, the shortening of colon length as well as the histopathologic improvement. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF, IL-1β, IL-6, IL-18, IL-17A and IFN-γ, were markedly suppressed by MALT1 inhibitors. The underlying mechanisms for the protective effect of MALT1 inhibitors in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in macrophages. The in vitro study showed that MALT1 inhibitors decreased production of IL-1β/IL-18 in phorbol myristate acetate-differentiated THP-1 cells and bone marrow derived macrophage via suppressing the activation of NF-κB and NLRP3 inflammasome. Taken together, our results demonstrated that inhibition of the protease activity of MALT1 might be a viable strategy to treat inflammatory bowel disease and the NLRP3 inflammasome and NF-κB activation are critical components in MALT1 signaling cascades in this disease model.

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MALT1 inhibitors prevent the development of DSS-induced experimental colitis in mice via inhibiting NF-κB and NLRP3 inflammasome activation

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