IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia.

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-κB and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) from microglia in an NF-κB-dependent manner. This expression also partially requires the intermediate production of TNF-α and subsequent NF-κB activation via TNF-R1. We also demonstrate that OSM-induced TNF-α production from microglia is neurotoxic. The IL-12 family member, IL-27, suppresses OSM-mediated TNF-α and iNOS expression at the transcriptional level by inhibiting activation of the NF-κB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the pro-inflammatory effects of OSM in microglia, and also identify IL-27 as a novel inhibitor of inflammatory processes in these cells.

在多发性硬化症（MS）、艾滋病相关神经认知障碍（HAND）和胶质母细胞瘤（GBM）中观察到抑瘤素M（OSM，一种白细胞介素 - 6家族细胞因子）水平升高；然而，其在中枢神经系统内的作用尚未得到充分了解。OSM主要以细胞类型特异性的方式通过激活JAK/STAT、NF - κB和/或MAPK通路来调节基因表达。在我们的研究中，OSM以NF - κB依赖的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TNF - α的中间产物以及随后通过TNF - R1激活NF - κB。我们还证明了OSM诱导小胶质细胞产生的TNF - α具有神经毒性。白细胞介素 - 12家族成员白细胞介素 - 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，并挽救由OSM刺激的小胶质细胞诱导的神经毒性。这些研究首次证明了OSM在小胶质细胞中的促炎作用，并且还确定白细胞介素 - 27是这些细胞中炎症过程的一种新型抑制剂。