Capsaicin indirectly regulates TRPA1 via the arachidonic acid cascade, resulting in TJ opening

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2023-12, Vol.88 (1), p.44-52
• Main Authors: Kanda, Yusuke, Mukaiyama, Minagi, Yamasaki, Yohei, Usui, Takeo, Nagumo, Yoko
• Format: Article
• Language: English
• Subjects: Arachidonic Acid - metabolism; Arachidonic Acid - pharmacology; Calcium - metabolism; Capsaicin - pharmacology; Cyclooxygenase 2 - genetics; Phospholipases A2
• ISSN: 1347-6947; 1347-6947
• DOI: 10.1093/bbb/zbad145

ABSTRACT Capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. We previously revealed that TRPA1 is involved in the capsaicin-induced Ca2+ influx and TJ permeability increase, although there are no reports that capsaicin directly activates TRPA1. In this study, we investigated the upstream factors of TRPA1 using RNA-seq analysis, and found that the cyclooxygenase 2 (COX2) gene was upregulated by capsaicin. Cyclooxygenase 2 converts arachidonic acid (AA), a metabolite by phospholipase A2 (PLA2), to prostaglandins. Prostaglandin E2 (PGE2) production was stimulated by capsaicin, and capsaicin-induced Ca2+ influx was effectively inhibited by PLA2 and COX2 inhibitors. The AA-induced TJ permeability increase was inhibited by a TRPA1 antagonist, but the capsaicin- and AA-induced TJ permeability increases were hardly inhibited by a COX2 inhibitor. These results suggest that capsaicin-induced PLA2 activation and AA production are the important steps for the TJ permeability increase. Graphical Abstract Graphical Abstract Capsaicin induces tight junction opening TRPA1-dependently with activating phospholipase A2 and upregulating cyclooxygenase 2 gene.