Inhibitory effect of 5-Pyridin-2-ylmethylene-6,7-dihydro-5H-benzo[b]thiophen-4-one (PT-2-318) on NF-kB and AP-1 activation in macrophages (CAM5P.235)

Abstract

Abstract TGF-beta activated kinase1 (TAK1) has been reported to play an essential role in pro-inflammatory cellular signaling pathway. Activated TAK1 phosphorylates IkB kinase β (IKKβ), leading to NF-kB activation. Nuclear factor-kB (NF-kB) is a ubiquitous transcriptional factor that controls the expression of genes involved in immune responses. Here, treatment with 5-Pyridin-2-ylmethylene-6,7-dihydro-5H-benzo[b]thiophen-4-one (PT-2-318) inhibited not only autophosphorylation of TAK1 but also acute liver injury of E.coli LPS/D-galactosamine-challenged mice. As a mechanism, PT-2-318 directly inhibited autophosphorylation of TAK1. So, phosphorylation of both IkB and MAPKs was inhibited. Also, LPS-induced NF-kB and AP-1 promotor activity in lipololysaccharides (LPS)-stimulated macrophages RAW 264.7 was inhibited by blocked TAK1. As TAK1 was blocked, PT-2-318 attenuated LPS-induced mRNA expression of cytokines (IL-1β, TNF-α). On the other hand, PT-2-318 did not inhibit phosphorylation of IRAK4 and degradation of IRAK1. in vivo, intravenous treatment with PT-2-318 protected against LPS/GalN-induced acute liver failure in C57/BL7 mice. These results suggest that PT-2-318 might be considered as a potential agents for the treatment of inflammatory diseases.