Oncostatin M (OSM) primes IL-13- and IL-4-induced eotaxin responses in fibroblasts: regulation of the type-II IL-4 receptor chains IL-4Ralpha and IL-13Ralpha1.
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.
Department of Pathology and Molecular Medicine, and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Dominik K
DK
Fritz
Christine
C
Kerr
Fernando
F
Botelho
Martin
M
Stampfli
Carl D
CD
Richards
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018793:Interleukin-13 / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D053683:Oncostatin M / Q000494:pharmacology / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D016207:Cytokines; D004791:Enzyme Inhibitors; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D053683:Oncostatin M; D015847:Interleukin-4; D003513:Cycloheximide; D048049:Extracellular Signal-Regulated MAP Kinases