Premium
Oncostatin M Regulation of Interleukin‐6 Expression in Astrocytes
Author(s) -
Van Wagoner Nicholas J,
Choi Chulhee,
Repovic Pavle,
Benveniste Etty N
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0750563.x
Subject(s) - oncostatin m , leukemia inhibitory factor receptor , leukemia inhibitory factor , microbiology and biotechnology , mapk/erk pathway , astrocyte , signal transduction , biology , cytokine , p38 mitogen activated protein kinases , tumor necrosis factor alpha , chemistry , interleukin 6 , immunology , endocrinology , central nervous system
Oncostatin M (OSM) is a member of the interleukin (IL)‐6 family of cytokines and has both pro‐ and anti‐inflammatory properties. Of interest, OSM has functional effects within the CNS. We have shown recently that OSM can modulate expression of the cytokine IL‐6 in astrocytes. Herein we characterize the molecular mechanisms and signaling cascades involved in this response. OSM induces IL‐6 protein expression in a dose‐ and time‐dependent manner in astrocytes. In addition, OSM can synergize with the cytokines tumor necrosis factor‐α, IL‐1β, and transforming growth factor‐β for enhanced IL‐6 expression. Using neutralizing antibodies to gp 130, the OSM receptor (OSMR), and the leukemia inhibitory factor receptor (LIFR), we document that OSM exclusively uses the OSMR/gp 130 heterodimer in signaling events, rather than the LIFR/gp 130 heterodimer. Kinetic analysis of OSM‐induced IL‐6 mRNA reveals two up‐regulatory events. The first, peaking at 1 h, is transient, does not require protein synthesis, and is regulated at the transcriptional level. The second, peaking between 6 and 8 h, is prolonged and sensitive to puromycin, suggesting a requirement for de novo protein synthesis, and also is transcriptionally regulated. OSM‐induced IL‐6 mRNA and protein expression is inhibited by the mitogen‐activated protein kinase (MAPK) inhibitors U0126 and SB202190, suggesting a requirement for the MAPKs ERK1/2 and p38 in this response. Finally, we show that the MAPKs ERK1/2 and p38 are activated by OSM in astrocytes and that this activation is reduced by the MAPK inhibitors. These data demonstrate that OSM induces IL‐6 expression in astrocytes and that the MAPKs ERK1/2 and p38 participate in this response.