RRC ID 82498
Author Ishii K, Naito K, Tanaka D, Koto Y, Kurata K, Shimizu H.
Title Molecular Mechanisms of Skatole-Induced Inflammatory Responses in Intestinal Epithelial Caco-2 Cells: Implications for Colorectal Cancer and Inflammatory Bowel Disease.
Journal Cells
Abstract Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in intestinal epithelial cells significantly contribute to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Given our previous findings that TNF-α is upregulated in intestinal epithelial Caco-2 cells induced by skatole, a tryptophan-derived gut microbiota metabolite, the present study aimed to explore the relationship between skatole and IL-6, alongside TNF-α. Skatole elevated the promoter activity of IL-6 as well as TNF-α, and increased IL-6 mRNA expression and protein secretion. In addition to activating NF-κB, the NF-κB inhibitor BAY 11-7082 reduced skatole-induced cell survival and the mRNA expression of IL-6 and TNF-α. NF-κB activation was attenuated by the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 and the p38 inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. U126 and SB203580 also decreased the skatole-induced increase in IL-6 expression. When skatole-induced AhR activation was inhibited by CH223191, in addition to promoting NF-κB activation, IL-6 expression was enhanced in a manner similar to that previously reported for TNF-α. Taken together, these results suggest that skatole-elicited NF-κB activation induces IL-6 and TNF-α expression, although AhR activation partially suppresses this process. The ability of skatole to increase the expression of IL-6 and TNF-α may significantly affect the development and progression of these diseases. Moreover, the balance between NF-κB and AhR activation appears to govern the skatole-induced increases in IL-6 and TNF-α expression. Therefore, the present findings provide new insights into the mechanisms linking tryptophan-derived gut microbiota metabolites with colorectal disease.
Volume 13(20)
Published 2024-10-18
DOI 10.3390/cells13201730
PII cells13201730
PMID 39451248
PMC PMC11505633
MeSH Caco-2 Cells Colorectal Neoplasms* / metabolism Colorectal Neoplasms* / pathology Epithelial Cells / drug effects Epithelial Cells / metabolism Epithelial Cells / pathology Humans Inflammation / metabolism Inflammation / pathology Inflammatory Bowel Diseases* / metabolism Inflammatory Bowel Diseases* / pathology Interleukin-6* / metabolism Intestinal Mucosa / drug effects Intestinal Mucosa / metabolism Intestinal Mucosa / pathology MAP Kinase Signaling System / drug effects NF-kappa B* / metabolism Nitriles / pharmacology Signal Transduction / drug effects Sulfones / pharmacology Tumor Necrosis Factor-alpha* / metabolism
Resource
Human and Animal Cells CACO-2(RCB0988)
DNA material pGL4-phTNF (RDB07310) pGL4-phIL6 (RDB07313)