ML365 inhibits lipopolysaccharide-induced inflammatory responses via the NF-κB signaling pathway

Abstract

ML365 is a selective inhibitor of the twik-related acid-sensitive potassium channel 1/two-pore domain channel subfamily k member 3 two-pore domain potassium channel. There are no functional studies of the relationship between ML365 and inhibition of inflammation. In this study, we evaluated the anti-inflammatory effect of ML365 on lipopolysaccharide (LPS)-induced inflammation and elucidated the possible mechanism. ML365 showed no cytotoxicity and did not induce apoptosis on RAW264.7 cells and inhibited nitric oxide production. ML365 suppressed the release of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1β measured using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction assays. LPS-induced activation and co-localization of NF-κB was inhibited by ML365 pre-treatment. ML365 inhibited the protein expression of Erk, p38 and Jnk. In vivo, ML365 appeared to prevent pathological damages in the LPS-induced endotoxin shock model. These findings suggest that ML365 inhibits LPS-induced inflammatory responses by regulating the NF-κB signaling pathway.