2-Hydroxycircumdatin C inhibits LPS-induced BV2 cells inflammatory response via down-regulation of TLR4-mediated NF-κB/MAPK and JAK2/STAT3 pathways

2-Hydroxycircumdatin C通过抑制TLR4/NF-κB/MAPK和JAK2/STAT3通路对脂多糖诱导BV2小胶质细胞发挥抗炎作用

2-Hydroxycircumdatin C(2-HCC) is a circumdatin-type alkaloid isolated from a coral-associated fungus Aspergillus ochraceus LZDX-32-15.In the present study,we aimed to assess the neuroprotective effects of 2-HCC on the microglia-mediated inflammatory response as well as underlining molecular mechanisms.2-HCC could significantly down-regulate the overproduction of tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) induced by lipopolysaccharide(LPS) both in BV2 cells and primary microglial cells without affecting cell viability.In addition,2-HCC exerted obvious neuroprotective effects against inflammatory injury in neurons when cocultured with LPS-induced microglia.Mechanism investigation indicated that the anti-inflammatory effect of 2-HCC involved the inhibition of inducible nitric oxide synthase(iNOS) and cyclooxygenase 2(COX-2) and alleviation of the LPS-induced TLR4-NF-κB/MAPK pathway.Furthermore,2-HCC treatment attenuated LPS-induced activation of the JAK2/STAT3 pathway.In conclusion,these results indicated that the anti-inflammatory and neuroprotective properties of 2-HCC,at least partially,depended upon TLR4-NF-κB/MAPK and JAK2/STAT3 signaling pathways.

2-Hydroxycircumdatin C(2-HCC)是从珊瑚附生真菌赭曲霉(Aspergillus ochraceus LZDX-32-15)中分离出来的一种喹唑啉苯并二氮杂[艹卓]生物碱。本文研究了2-HCC抑制小胶质细胞炎症反应的作用机制及其对神经元细胞的保护作用。在LPS诱导的小鼠小胶质BV2细胞炎症反应中,2-HCC抑制LPS诱导的BV2细胞产生的肿瘤坏死因子(TNF-α)和白细胞介素(IL-1β)的分泌,以及诱导型一氧化氮合酶(iNOS)和环氧氧酶2(COX-2)的表达。此外,通过原代小胶质细胞及原代神经元细胞共培养实验发现,2-HCC能够抑制LPS诱导的共培养体系中原代小胶质细胞炎性因子的过度表达和释放,进而起到保护原代神经元细胞的作用。进一步研究发现,2-HCC通过抑制LPS诱导的TLR4/NF-κB/MAPK和JAK2/STAT3信号通路发挥抗炎作用。综上所述,2-HCC能够通过下调BV2细胞中TLR4/NF-κB/MAPK和JAK2/STAT3信号传导通路,抑制炎症反应从而发挥神经保护作用。