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Inhibition of IRAK 1/4 alleviates colitis by inhibiting TLR 4/NF-κB 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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9589302/ https://www.ncbi.nlm.nih.gov/pubmed/35699749 http://dx.doi.org/10.17305/bjbms.2022.7348 |
Sumario: | 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-κB 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 mucin1/2. 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-κB p65, including the phosphorylation of IκBα 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-κB pathway, reducing inflammation, and maintaining the integrity of the colonic barrier. |
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