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1
Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
Oncostatin M (OSM) is an IL-6/LIF cytokine family member whose role has been identified in a range of biological activities in vitro, including up-regulation of inflammatory gene expression and regulation of connective tissue metabolism. However, the mechanisms through which OSM regulates cellular responses are not completely understood. In this study, we show that activation of the calcium-independent or novel protein kinase C (PKC) isoform PKC
is a critical event during OSM-mediated up-regulation of IL-6 expression in murine fibroblasts. The pan-PKC inhibitor GF109203X (bisindolylmaleimide I) reduced secretion of IL-6; however, use of Go6976, an inhibitor of calcium-dependent PKC enzymes, did not. The PKC-selective inhibitory compound rottlerin abrogated expression of IL-6 transcript and protein, but only reduced PKC activity when used at higher concentrations as determined by kinase activity assay, suggesting rottlerin may inhibit IL-6 expression in a PKC-independent manner. However, silencing of PKC protein expression, but not the related novel isoform PKC
, by use of RNA interference (i.e., small interfering RNA) demonstrated that PKC is required for murine OSM (mOSM) induction of IL-6 protein secretion. Furthermore, inhibition of PI3K by use of LY294002 reduces expression of IL-6 at both the mRNA and protein level in murine fibroblasts, and we suggest that PI3K is required for activation of PKC. Knockdown of phosphoinositide-dependent kinases PDK-1 or Akt1 using small interfering RNA strategies did not influence mOSM-induced IL-6 expression, suggesting mOSM uses a PI3K–PKC pathway of activation independent of these kinases. Our findings illustrate a novel signaling network used by mOSM that may be important for its mediation of inflammatory processes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by funding from the Canadian Institutes for Health Research and the Arthritis Society of Canada.
2 Address correspondence and reprint requests to Dr. Carl D. Richards, Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, Michael G. DeGroote Centre for Learning and Discovery, Room 4020, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. E-mail address: richards{at}mcmaster.ca
3 Abbreviations used in this paper: OSM, oncostatin M; mOSM, murine OSM; MLF, murine lung fibroblast; PKC, protein kinase C; PDK-1, phosphoinositide-dependent kinase-1; PDGF, platelet-derived growth factor; siRNA, small interfering RNA; Ct, threshold cycle.
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