Inhibition of IRAK 1/4 alleviates colitis by inhibiting TLR 4/NF-[kappa]B pathway and protecting the intestinal barrier

Interleukin-1 receptor-associated kinase 1/4 (IRAK1/4) is the main kinase of the toll-like receptor (TLR)-mediated pathway, considered a new target for treating inflammatory diseases. Studies showed a significant correlation between TLRs and inflammatory responses in ulcerative colitis. Therefore, i...

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Bibliographic Details
Published in:Bosnian journal of basic medical sciences 2022-11, Vol.22 (6), p.872
Main Authors: Yan, Bo, Li, Xiangjie, Zhou, Linxiang, Qiao, Yuqing, Wu, Jing, Zha, Lanlan, Liu, Peilu, Peng, Shuai, Wu, Baixin, Yu, Xiaoyun, Shen, Lei
Format: Article
Language:English
Subjects:
Development and progression
Drug therapy
Health aspects
Physiological aspects
Protein kinases
TLR4
Ulcerative colitis
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Summary:Interleukin-1 receptor-associated kinase 1/4 (IRAK1/4) is the main kinase of the toll-like receptor (TLR)-mediated pathway, considered a new target for treating inflammatory diseases. Studies showed a significant correlation between TLRs and inflammatory responses in ulcerative colitis. Therefore, in this study, after inducing experimental colitis in mice with 3% dextran sulfate sodium (DSS), different concentrations of IRAK1/4 inhibitors were administered intraperitoneally. Then, the disease activity index was assessed, including the degree of pathological damage, by HE staining. Subsequently, while Western blotting detected the TLR4/NF-[kappa]B pathway and intestinal barrier protein expression (Zonula-1, Occludin, Claudin-1, JAM-A), real-time polymerase chain reaction detected the mRNA expression levels of IRAK1/4 and mucini/2. Furthermore, the expression levels of Zonula-1 and occludin were detected by immunofluorescence, including the plasma FITC-dextran 4000 concentration, to evaluate intestinal barrier permeability. However, ELISA measured the expression of inflammatory factors to reflect intestinal inflammation in mice. Investigations showed that the IRAK 1/4 inhibitor significantly reduced clinical symptoms and pathological DSS-induced colitis damage in mice and then inhibited the cytoplasmic and nuclear translocation of NF-[kappa]B p65, including the phosphorylation of I[kappa]Bia and reduction in downstream inflammatory factor production. Therefore, we established that the IRAK1/4 inhibitor effectively improves colitis induced by DSS, partly by inhibiting the TLR4/NF-[kappa]B pathway, reducing inflammation, and maintaining the integrity of the colonic barrier. KEYWORDS: Interleukin-1 receptor-associated kinase 1/4; ulcerative colitis; TLR 4/NF-[kappa]B; intestinal barrier
ISSN:1512-8601
DOI:10.17305/bjbms.2022.7348