IL-27 Inhibits OSM-mediated TNF-α 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.