Regulation of tissue inhibitor of metalloproteinase-1 in fibroblasts and acute phase proteins in hepatocytes in vitro by mouse oncostatin M, cardiotrophin-1, and IL-6.
Mouse oncostatin M (mOSM) has been recently cloned; however, its full spectrum of biologic functions has not been defined. To assess its potential role in inflammation, we have tested the activity of mOSM in vitro in regulation of fibroblasts and hepatic cells. At concentrations of 10 and 20 ng/ml, mOSM stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA in NIH-3T3 mouse embryonic fibroblasts, rat lung fibroblasts, and rat synovial fibroblasts, whereas mouse cardiotrophin-1 (mCT-1) or human OSM (hOSM) did not. Similarly, only mOSM was able to induce transcription of chloramphenicol acetyl-transferase (CAT) in NIH-3T3 cells transfected with a minimal TIMP-1 promoter/CAT construct. Mouse OSM had strong action inducing primary rat hepatocyte cultures to produce acute phase proteins; however, mOSM was very weak in its ability to stimulate acute phase protein synthesis in rat H35 cells or human HepG2 cells, which was consistent with weak STAT activation in H35 cells and HepG2 cells. Binding studies showed that NIH-3T3 cells possessed high affinity binding sites for mOSM, but rat H35 cells did not. On the other hand, mCT-1 and mouse IL-6 induced strong STAT activation as well as marked increases in acute phase protein production by H35 cells. These results indicate that mOSM does not share a functional receptor with mCT-1 or hOSM in mouse and rat cells and that hOSM does not activate the putatively specific OSM receptor on mouse or rat cells. These results also suggest that mOSM is an important cytokine in inflammation, through modulation of fibroblast function as well as hepatocyte responses.
Richards
C D
CD
Department of Pathology, McMaster University, Hamilton, Ontario, Canada. richards@fhs.csu.mcmaster.ca
Kerr
C
C
Tanaka
M
M
Hara
T
T
Miyajima
A
A
Pennica
D
D
Botelho
F
F
Langdon
C M
CM
D016475:3T3 Cells; D000209:Acute-Phase Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008113:Liver Neoplasms / Q000473:pathology; D008168:Lung / Q000166:cytology; D051379:Mice; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology* / Q000502:physiology; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000378:metabolism; D053677:Receptors, Oncostatin M; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013045:Species Specificity; D013583:Synovial Membrane / Q000166:cytology; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D015850:Interleukin-6; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators; D053683:Oncostatin M; C092073:cardiotrophin 1; D015500:Chloramphenicol O-Acetyltransferase