METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice

Abstract

The inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. Dysregulated cytokine secretion and signal transduction mechanisms via intestinal epithelial cells are involved in IBD pathogenesis, in which the transcription factor NF-κB plays a critical role. In this study, METTL3, which plays a key role in inflammation regulation, has been recognized significantly up-regulated in IBD samples, DSS-induced IBD mice, and LPS-treated MODE-K cells. Within LPS-treated MODE-K cells, METTL3 knockdown promoted cell viability, inhibited cell apoptosis, decreased apoptotic caspase3/9 cleavage, and decreased the levels of proinflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-18) and inflammatory enzymes (COX-2 and iNOS). Under the same conditions, METTL3 knockdown inhibited, whereas METTL3 overexpression promoted p65 phosphorylation in MODE-K cells; NF-κB inhibitor JSH-23 partially abolished the promotive effects of METTL3 overexpression upon p65 phosphorylation. Consistently, the effects of METTL3 overexpression upon LPS-stimulated MODE-K cells were partially abolished by JSH-23. Lastly, METTL3 knockdown in DSS-induced IBD mice significantly ameliorated DSS-induced IBD and inhibited DSS-induced p65 phosphorylation. In conclusion, METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice. The NF-κB signaling might be involved, and the regulatory mechanism remains to be investigated in our future study.

METTL3‐mediated m6A modification of circPRKAR1B promotes Crohn's colitis by inducing pyroptosis via autophagy inhibition

“…METTL3, a well‐known m 6 A modification writer, is a necessary catalytic subunit modulating m 6 A modification 47 . METTL3 was upregulated in CD colon tissues compared to NC tissues, consistent with Yang et al 48 . The close m 6 A modification and inflammation connection have attracted much attention.…”

“…46 METTL3, a wellknown m 6 A modification writer, is a necessary catalytic subunit modulating m 6 A modification. 47 METTL3 was upregulated in CD colon tissues compared to NC tissues, consistent with Yang et al 48 The close m 6 A modification and inflammation connection have attracted much attention. A previous study in human dental pulp cells has shown that METTL3 can suppress the inflammatory response caused by LPS by modulating the alternate splicing of MyD88.…”

Alleviating effect of Nexrutine on mucosal inflammation in mice with ulcerative colitis: Involvement of the RELA suppression

“…41 Mounting evidence has demonstrated the beneficial effects of RELA (p65) on the intestinal epithelial cell survival, inflammation resolution, and intestinal barrier maintenance in UC. [42][43][44] In this study, we identified that the artificial upregulation of RELA, both in the 3% DSS-induced mice and LPS-induced NCM-460 cells, significantly blocked the alleviating roles of Nexrutine from all aspects.…”

Hyper α2,6‐Sialylation Promotes CD4+ T‐Cell Activation and Induces the Occurrence of Ulcerative Colitis

“…LPS has also been reported to be associated with UC. [ 31 ] LPS upregulated ST6GAL1 gene expression. An increase in pro‐inflammatory cytokines and a decrease in anti‐inflammatory cytokines often lead to UC.…”