title: Chaetoglobosin Fex from the marine-derived endophytic fungus inhibits induction of inflammatory mediators via Toll-like receptor 4 signaling in macrophages.
abstract: Chaetoglobosin Fex (Cha Fex), a cytochalasan-based alkaloid, was isolated from marine-derived endophytic fungus Chaetomium globosum QEN-14. The knowledge of its biological function is still limited. We investigated the effects and mechanism of Cha Fex on inflammatory mediators via Toll-like receptor 4 (TLR4) signaling in macrophages. Lipopolysaccharide (LPS), TLR4 ligand, was therefore designed to active TLR4 signaling pathway, and Cha Fex significantly inhibited the LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) in peritoneal macrophages and murine macrophage cell line RAW264.7. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) detection also found that Cha Fex down-regulated the mRNA expressions of these pro-inflammtory cytokines. Moreover, Cha Fex significantly attenuated the LPS-stimulated degradation of inhibitory kappa B-alpha and the subsequent translocation of the p65 subunit of nuclear factor-kappa B (NF-κB) to the nucleus. Cha Fex also reduced the phosphorylations of extracellular-signal-related kinase (ERK1/2), p38, and c-Jun N-terminal kinase (JNK1/2). Furthermore, we confirmed that Cha Fex didn't affect LPS binding to the RAW264.7 cells and human monocytes, while Cha Fex was able to inhibit the increase of membrane-associated CD14 (mCD14) expression both on RAW cells and human monocytes induced by LPS to a certain degree. These results suggest that the anti-inflammatory property of Cha Fex may be attributed to NF-κB inhibition as well as the negative regulation of ERK1/2, p38, and JNK1/2 phosphorylations. On the other hand, these inhibitory effects may also be due to the blocking of mCD14 expression.
authors: Immunology and Reproductive Biology Lab & Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing 210093, P. R. China.
authors: Huan
authors: H
authors: Dou
authors: Yuxian
authors: Y
authors: Song
authors: Xianqin
authors: X
authors: Liu
authors: Wei
authors: W
authors: Gong
authors: Erguang
authors: E
authors: Li
authors: Renxiang
authors: R
authors: Tan
authors: Yayi
authors: Y
authors: Hou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins / Q000276:immunology; D026121:Indole Alkaloids / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009183:Mycotoxins / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D026121:Indole Alkaloids; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D009183:Mycotoxins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; C019290:chaetoglobosins; D020928:Mitogen-Activated Protein Kinases