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

Moose oncostatin M (mOSM) has been recently cloned; however, its full spectrum of biologic functions has not been defined. To assess its pot ential role in inflammation, we have tested the activity of mOSM in vi tro in regulation of fibroblasts and hepatic cells, At concentrations of 10 and 20 ng/ml, mOSM stimulates tissue inhibitor of metalloprotein ase-1 (TIMP-1) mRNA in NIH-3T3 mouse embryonic fibroblasts, rat lung f ibroblasts, and rat synovial fibroblasts, whereas mouse cardiotrophin- 1 (mCT-1) or human OSM (hOSM) did not. Similarly, only mOSM was able t o induce transcription of chloramphenicol acetyltransferase (CAT) in N IH-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 ab ility to stimulate acute phase protein synthesis in rat H35 cells or h uman HepG2 cells, which was consistent with weak STAT activation in H3 5 cells and HepG2 cells. Binding studies showed that NIH-3T3 cells pos sessed 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 activati on as well as marked increases in acute phase protein production by H3 5 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 cell s. These results also suggest that mOSM is an important cytokine in in flammation, through modulation of fibroblast function as well as hepat ocyte responses.