Oncostatin M regulation of interleukin-6 expression in astrocytes: Biphasic regulation involving the mitogen-activated protein kinases ERK1/2 and p38

Oncostatin M (OSM) is a member of the interleukin (IL)-6 family of cytokine s and has both pro- and antiinflammatory properties. Of interest, OSM has f unctional effects within the CNS. We have shown recently that OSM can modul ate expression of the cytokine IL-6 in astrocytes, Herein we characterize t he molecular mechanisms and signaling cascades involved in this response. O SM induces IL-6 protein expression in a dose- and time-dependent manner in astrocytes, In addition, OSM can synergize with the cytokines tumor necrosi s factor-alpha, IL-1 beta, and transforming growth factor-beta for enhanced IL-6 expression. Using neutralizing antibodies to gp130, the OSM receptor (OSMR), and the leukemia inhibitory factor receptor (LIFR), we document tha t OSM exclusively uses the OSMR/gp130 heterodimer in signaling events, rath er than the LIFR/gp130 heterodimer. Kinetic analysis of OSM-induced IL-6 mR NA reveals two up-regulatory events. The first, peaking at 1 h, is transien t, does not require protein synthesis, and is regulated at the transcriptio nal level. The second, peaking between 6 and 8 h, is prolonged and sensitiv e to puromycin, suggesting a requirement for de novo protein synthesis, and also is transcriptionally regulated. OSM-induced IL-6 mRNA and protein exp ression is inhibited by the mitogen-activated protein kinase (MAPK) inhibit ors U0126 and SB202190, suggesting a requirement for the MAPKs ERK1/2 and p 38 in this response. Finally, we show that the MAPKs ERK1/2 and p38 are act ivated by OSM in astrocytes and that this activation is reduced by the MAPK inhibitors. These data demonstrate that OSM induces IL-6 expression in ast rocytes and that the MAPKs ERK1/2 and p38 participate in this response.