Immunology and Reproductive Biology Lab & Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing 210093, P. R. China.
Biol Pharm Bull. 2011;34(12):1864-73. doi: 10.1248/bpb.34.1864.
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.
Chaetoglobosin Fex（Cha Fex）是一种来源于海洋来源的内生真菌 Chaetomium globosum QEN-14 的细胞松弛素生物碱。其生物学功能的知识仍然有限。我们通过 Toll 样受体 4（TLR4）信号通路研究了 Cha Fex 对炎症介质的影响及其机制在巨噬细胞中。因此，设计了脂多糖（LPS），TLR4 配体，以激活 TLR4 信号通路，Cha Fex 显著抑制了 LPS 诱导的腹腔巨噬细胞和小鼠巨噬细胞系 RAW264.7 中肿瘤坏死因子-α（TNF-α），白细胞介素 6（IL-6）和单核细胞趋化蛋白-1（MCP-1）的产生。实时逆转录聚合酶链反应（实时 RT-PCR）检测还发现，Cha Fex 下调了这些促炎细胞因子的 mRNA 表达。此外，Cha Fex 显著减弱了 LPS 刺激的抑制κB-α的降解以及随后核因子-κB（NF-κB）p65 亚基向核内的易位。Cha Fex 还降低了细胞外信号相关激酶（ERK1/2），p38 和 c-Jun N 端激酶（JNK1/2）的磷酸化。此外，我们证实 Cha Fex 不影响 LPS 与 RAW264.7 细胞和人单核细胞的结合，而 Cha Fex 能够在一定程度上抑制 LPS 诱导的 RAW 细胞和人单核细胞膜相关 CD14（mCD14）表达的增加。这些结果表明，Cha Fex 的抗炎特性可能归因于 NF-κB 的抑制以及 ERK1/2，p38 和 JNK1/2 磷酸化的负调节。另一方面，这些抑制作用也可能是由于阻断了 mCD14 的表达。
