A Tubulin Inhibitor, N-(5-Benzyl-1,3-thiazol-2-yl)-3-(furan-2-yl)prop-2-enamide, Induces Anti-inflammatory Innate Immune Responses to Attenuate LPS-mediated Septic Shock

Abstract

The anti-inflammatory effect of a tubulin inhibitor, N-(5-benzyl-1,3-thiazol-2-yl)-3-(furan-2-yl)prop-2-enamide (1), on innate immune responses remains unclear. Thus, we investigated the effect of I on the immune responses mediated by lipopolysaccharide (LPS). The in vitro addition of I to dendritic cells and macrophages dose-dependently reduced tumor necrosis factor alpha production elicited by LPS stimulation. Additionally, the stimulation of natural killer (NK) and natural killer T (NKT) cells with 1 resulted in the decrease of interferon gamma (IFN gamma) induced by LPS treatment. Moreover, 1 substantially reduced interleukin 12 in dendritic cells (DC) as well as IFN gamma in NKDCs induced by LPS in vitro. Furthermore, the in vivo administration of 1 ameliorated LPS/D-galactosamine-induced endotoxic lethality in mice. Taken together, our results demonstrate for the first time that 1 possesses anti-inflammatory properties, most notably by modulating LPS-induced innate immune responses. Therefore, 1 might have therapeutic potential for the treatment of inflammation-mediated diseases such as sepsis.