title: Mycoepoxydiene inhibits lipopolysaccharide-induced inflammatory responses through the suppression of TRAF6 polyubiquitination [corrected].
abstract: Mycoepoxydiene (MED) is a polyketide isolated from a marine fungus associated with mangrove forests. MED has been shown to be able to induce cell cycle arrest and cancer cell apoptosis. However, its effects on inflammatory response are unclear. Herein we showed that MED exhibited inhibitory effect on inflammatory response induced by lipopolysaccharide (LPS). MED significantly inhibited LPS-induced expression of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and nitric oxide (NO) in macrophages. MED inhibited LPS-induced nuclear translocation of nuclear factor (NF)-κB (NF-κB) p65, IκB degradation, IκB kinase (IKK) phosphorylation, and the activation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38, suggesting that MED blocks the activation of both NF-κB and mitogen-activated protein kinase (MAPK) pathways. Furthermore, the effects of MED on LPS-induced activation of upstream signaling molecules such as transforming growth factor-β-activated kinase 1 (TAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6) and IL-1 receptor associated kinases1 (IRAK1) were investigated. MED significantly inhibited TAK1 phosphorylation and TRAF6 polyubiquitination, but not IRAK1 phosphorylation and TRAF6 dimerization, indicating that MED inhibits LPS-induced inflammatory responses at least in part through suppression of TRAF6 polyubiquitination. Moreover, MED protected mice from LPS-induced endotoxin shock by reducing serum inflammatory cytokines. These results suggest that MED is a potential lead compound for the development of a novel nonsteroidal anti-inflammatory drug.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Tenghui
authors.initials: T
authors.lastname: Chen
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yaojian
authors.initials: Y
authors.lastname: Huang
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
authors.forename: Chundong
authors.initials: C
authors.lastname: Yu
mesh_terms: D000818:Animals; D001831:Body Temperature; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D011753:Pyrones / Q000494:pharmacology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D001952:Bridged-Ring Compounds; D016207:Cytokines; D004731:Endotoxins; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D011753:Pyrones; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C476085:mycoepoxydiene; C507769:Irak1 protein, mouse