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 cytokines and has both pro- and antiinflammatory 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-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 that OSM exclusively uses the OSMR/gp130 heterodimer in signaling events, rather than the LIFR/gp130 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.
Publisher
LIPPINCOTT WILLIAMS WILKINS
Issue Date
2000-08
Language
ENG
Keywords

LEUKEMIA INHIBITORY FACTOR; TUMOR-NECROSIS-FACTOR; MHC GENE-EXPRESSION; VASOACTIVE-INTESTINAL-PEPTIDE; MESSENGER-RNA EXPRESSION; CLASS-II TRANSACTIVATOR; SOLUBLE IL-6 RECEPTOR; GROWTH-FACTOR-BETA; TGF-BETA; TNF-ALPHA

Citation

JOURNAL OF NEUROCHEMISTRY, v.75, no.2, pp.563 - 575

ISSN
0022-3042
DOI
10.1046/j.1471-4159.2000.0750563.x
URI
http://hdl.handle.net/10203/74775
Appears in Collection
BiS-Journal Papers(저널논문)
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