Skatole-induced p38 and JNK activation coordinately upregulates, whereas AhR activation partially attenuates TNFα expression in intestinal epithelial cells

• Published in: Bioscience, biotechnology, and biochemistry Vol. 87; no. 6; pp. 611 - 619
• Main Authors: Kurata, Koichi, Ishii, Katsunori, Koto, Yoshihito, Naito, Kazuma, Yuasa, Kana, Shimizu, Hidehisa
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 19.05.2023
• Subjects: Caco-2 Cells; Epithelial Cells - metabolism; Humans; Inflammatory Bowel Diseases - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Skatole - metabolism; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; intestinal epithelial cells; tryptophan metabolite; indole derivative; inflammation; gut microbiota
• ISSN: 1347-6947; 1347-6947
• DOI: 10.1093/bbb/zbad030

ABSTRACT Increased tumor necrosis factor α (TNFα) expression in intestinal epithelial cells (IECs) plays a major role in the development and progression of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The present study aimed to clarify the relationship between TNFα and skatole, a tryptophan-derived gut microbiota metabolite. The aryl hydrocarbon receptor (AhR) antagonist CH223191 promoted, whereas the p38 inhibitor SB203580 suppressed the increase in TNFα mRNA and protein expression induced by skatole in intestinal epithelial Caco-2 cells. The c-Jun N-terminal kinase (JNK) inhibitor SP600125 repressed only the increased TNFα protein expression, whereas the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 did not affect increased TNFα expression at any level. A neutralizing antibody against TNFα partially inhibited skatole-induced cell death. Overall, these results suggested that TNFα expression is increased by the concerted actions of skatole-activated p38 and JNK, and that TNFα exerts autocrine/paracrine actions on IECs despite partial suppression by activated AhR. Therefore, skatole might play an important role in the development and progression of IBD and CRC via increased TNFα expression. Graphical Abstract Graphical Abstract AhR partially attenuates but p38 and JNK coordinately upregulate skatole-induced expression of TNFα, which exerts autocrine/paracrine actions on IECs.