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 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-alpha, IL-1beta, and transforming growth factor-beta 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.
Van Wagoner
N J
NJ
Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Choi
C
C
Repovic
P
P
Benveniste
E N
EN
D000328:Adult; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D001254:Astrocytoma; D016207:Cytokines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics*; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D018121:Receptors, Cytokine / Q000502:physiology; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D006131:Growth Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; C508351:OSM protein, human; D010455:Peptides; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases