Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E2 (PGE2), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE2 production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1β, tumor necrosis factor-α, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE2 production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE2 production by OSM and IL-1β treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE2 synthesis. Of the enzymes involved in PGE2 biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1β. Nuclear run-on assays demonstrate that OSM and IL-1β synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1β. To effect synergy on the PGE2 level, OSM signals in part through its gp130/OSMRβ receptor, since neutralizing antibodies against gp130 and OSMRβ, but not LIFRβ, decrease PGE2 production in response to OSM plus IL-1β. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1β and OSM upregulation of COX-2 and PGE2, indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE2 amplification may be active in brain pathologies where both OSM and IL-1β are present, such as glioblastomas and multiple sclerosis. © 2003 Wiley-Liss, Inc.