Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Glia. 2010 Jul;58(9):1082-93. doi: 10.1002/glia.20989.
Elevated levels of Oncostatin M (OSM), an interleukin-6 family cytokine, have been observed in multiple sclerosis (MS), HIV-associated neurocognitive disorder (HAND), and glioblastoma (GBM); however, its effects within the CNS are not well understood. OSM regulates gene expression primarily by activating the JAK/STAT, NF-kappaB, and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) from microglia in an NF-kappaB-dependent manner. This expression also partially requires the intermediate production of TNF-alpha and subsequent NF-kappaB activation via TNF-R1. We also demonstrate that OSM-induced TNF-alpha production from microglia is neurotoxic. The IL-12 family member, IL-27, suppresses OSM-mediated TNF-alpha and iNOS expression at the transcriptional level by inhibiting activation of the NF-kappaB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the proinflammatory effects of OSM in microglia, and also identify IL-27 as a novel inhibitor of inflammatory processes in these cells.
细胞因子 Oncostatin M（OSM）水平升高与多发性硬化症（MS）、HIV 相关神经认知障碍（HAND）和胶质母细胞瘤（GBM）有关；然而，其在中枢神经系统（CNS）内的作用尚未完全阐明。OSM 通过以细胞类型特异性的方式激活 JAK/STAT、NF-κB 和/或 MAPK 通路，主要调节基因表达。在我们的研究中，OSM 以 NF-κB 依赖性方式诱导小胶质细胞产生促炎细胞因子肿瘤坏死因子-α（TNF-α）和诱导型一氧化氮合酶（iNOS）。这种表达也部分需要通过 TNF-R1 中间产生 TNF-α和随后的 NF-κB 激活。我们还证明 OSM 诱导小胶质细胞产生的 TNF-α具有神经毒性。IL-12 家族成员 IL-27 通过抑制 NF-κB 通路的激活，在转录水平上抑制 OSM 介导的 TNF-α和 iNOS 表达，并挽救 OSM 刺激的小胶质细胞引起的神经毒性。这些研究首次证明了 OSM 在小胶质细胞中的促炎作用，并确定了 IL-27 是这些细胞中炎症过程的一种新型抑制剂。
