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

✍ Scribed by Brandi J. Baker; Keun W. Park; Hongwei Qin; Xiangyu Ma; Etty N. Benveniste

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 521 KB
• Volume: 58
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/glia.20989

✦ Synopsis

Abstract

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 proinflammatory 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 proinflammatory effects of OSM in microglia, and also identify IL‐27 as a novel inhibitor of inflammatory processes in these cells. © 2010 Wiley‐Liss, Inc.