Abstract
Oncostatin M (OSM), a pleiotropic cytokine and a member of the gp130/IL-6 cytokine family, has been implicated in regulation of various chronic inflammatory processes. Previous work has shown that OSM induces eosinophil accumulation in mouse lungs in vivo and stimulates the eosinophil-selective chemokine eotaxin-1 synergistically with IL-4 in vitro. To examine the role of receptor regulation by OSM in synergistic eotaxin-1 responses, we here examine the modulation of the type-II IL-4 receptor (IL-4Ralpha and IL-13Ralpha1) by OSM and other gp130/IL-6 cytokine family members using NIH3T3 fibroblasts and primary mouse lung fibroblasts. We first show that OSM with either IL-13 or IL-4 synergistically induces eotaxin-1 expression in a dose-dependent fashion. Analysis of IL-4Ralpha expression at the protein (Western blot and FACS) and RNA (TAQMAN) levels showed that OSM markedly elevates expression by 3 h. OSM enhanced IL-13Ralpha1 mRNA and induced a smaller but detectable increase in total IL-13Ralpha1 protein. Priming fibroblasts with OSM for 6 h markedly enhanced subsequent IL-13 and IL-4-induced eotaxin-1 responses and STAT6 tyrosine-641 phosphorylation. Regulation of IL-4Ralpha by OSM was sensitive to inhibition of the PI3'K pathway by LY294002. These studies provide novel mechanistic insights in OSM role in regulation of synergistic eotaxin-1 responses and IL-4Ralpha expression in fibroblasts.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Membrane / metabolism
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Cells, Cultured
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Chemokine CCL11 / genetics
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Chemokine CCL11 / metabolism*
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Cycloheximide / pharmacology
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Cytokines / metabolism
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Cytokines / pharmacology
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Gene Expression / drug effects
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Gene Expression / genetics
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Interleukin-13 / pharmacology*
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Interleukin-13 Receptor alpha1 Subunit / genetics
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Interleukin-13 Receptor alpha1 Subunit / metabolism*
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Interleukin-4 / pharmacology*
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Interleukin-4 Receptor alpha Subunit / genetics
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Interleukin-4 Receptor alpha Subunit / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NIH 3T3 Cells
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Oncostatin M / pharmacology
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Oncostatin M / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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STAT6 Transcription Factor / genetics
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STAT6 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
Substances
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Ccl11 protein, mouse
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Chemokine CCL11
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Cytokines
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Enzyme Inhibitors
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Interleukin-13
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Interleukin-13 Receptor alpha1 Subunit
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Interleukin-4 Receptor alpha Subunit
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Phosphoinositide-3 Kinase Inhibitors
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Oncostatin M
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Interleukin-4
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Cycloheximide
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Extracellular Signal-Regulated MAP Kinases