PT  - JOURNAL ARTICLE
AU  - Yi Wang
AU  - Xiaoou Shan
AU  - Yuanrong Dai
AU  - Lili Jiang
AU  - Gaozhi Chen
AU  - Yali Zhang
AU  - Zhe Wang
AU  - Lili Dong
AU  - Jianzhang Wu
AU  - Guilong Guo
AU  - Guang Liang
TI  - Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2
AID  - 10.1124/jpet.115.222570
DP  - 2015 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 539--550
VI  - 353
IP  - 3
4099  - http://jpet.aspetjournals.org/content/353/3/539.short
4100  - http://jpet.aspetjournals.org/content/353/3/539.full
SO  - J Pharmacol Exp Ther2015 Jun 01; 353
AB  - Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various proinflammatory cytokines, remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through the myeloid differentiation protein 2 (MD2) and Toll-like receptor 4 (TLR4) complex, increase the production of inflammatory mediators. Our previous studies have found that a curcumin analog, L48H37 [1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)piperidin-4-one], was able to inhibit LPS-induced inflammation, particularly tumor necrosis factor α and interleukin 6 production and gene expression in mouse macrophages. In this study, a series of biochemical experiments demonstrate L48H37 specifically targets MD2 and inhibits the interaction and signaling transduction of LPS-TLR4/MD2. L48H37 binds to the hydrophobic region of MD2 pocket and forms hydrogen bond interactions with Arg90 and Tyr102. Subsequently, L48H37 was shown to suppress LPS-induced mitogen-activated protein kinase phosphorylation and nuclear factor κB activation in macrophages; it also dose dependently inhibits the cytokine expression in macrophages and human peripheral blood mononuclear cells stimulated by LPS. In LPS-induced septic mice, both pretreatment and treatment with L48H37 significantly improved survival and protected lung injury. Taken together, this work identified a new MD2 specific inhibitor, L48H37, as a potential candidate in the treatment of sepsis.