680C91, a small molecule inhibitor of TDO, suppresses production of IL-1β and IL-6 in LPS-stimulated murine macrophage cells

• Published in: 日本薬理学会年会要旨集 p. 2-P-087
• Main Authors: 西, 昭徳, 沈, 龍佑, 外角, 直樹
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2019
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.92.0_2-P-087

Tryptophan 2,3-dioxygenase (TDO), which converts tryptophan to kynurenine, is a rate-limiting enzyme of the kynurenine pathway. TDO has been reported to mediate immune responses in inflammatory diseases. Here, we report a novel pharmacological action of a well-known inhibitor of TDO, 680C91. The effects of 680C91 on the expression of LPS-stimulated pro-inflammatory cytokines were examined in Raw 264.7 cells and primary peritoneal macrophages prepared from wild-type and TDO knockout mice. In Raw264.7 cells and primary peritoneal macrophages prepared from wild-type mice, 680C91 significantly attenuated LPS-induced mRNA expression of IL-1β and IL-6, but not TNF-α. Interestingly, the inhibitory effects of 680C91 on LPS-induced mRNA expression of IL-1β and IL-6 were observed in primary peritoneal macrophages prepared from TDO knockout mice. In analyses of molecular mechanisms, we found that the phosphorylation of STAT3 and Akt induced by LPS was attenuated by 680C91. These observations suggest that 680C91 likely acts as an inhibitor of LPS-induced inflammatory responses in a TDO-independent manner via mechanisms involving STAT3 and Akt signaling.