ONCOSTATIN-M STIMULATES EXCESSIVE EXTRACELLULAR-MATRIX ACCUMULATION IN A TRANSGENIC MOUSE MODEL OF CONNECTIVE-TISSUE DISEASE

Oncostatin M (OM), a member of the IL-6 gene family, stimulates a vari ety of functions implicated in wound repair. Transgenic mice that expr ess this cytokine in islet beta-cells develop a connective tissue diso rder that typifies excessive healing with severe fibrosis and lymphocy tic infiltration. To compare this phenotype with the normal progressio n of connective tissue disease, we measured the expression patterns of genes encoding proinflammatory cytokines, fibrogenic cytokines, and E CM components by in situ hybridization. To test whether the OM effect was caused by its ability to regulate IL-6, we crossed the OM transgen e into IL-6-deficient mice. Our data suggest that the fibrosis in thes e animals is not a secondary consequence of inflammation, or IL-6 expr ession, but is a direct effect by OM on extracellular matrix productio n. In a separate experiment, we observed that OM could regulate vasoac tive intestinal peptide gene expression in the neurons that innervate the transgenic pancreas. This nerve healing response, in combination w ith its fibrogenic activity, suggests that OM functions downstream of inflammation in the wound repair cascade. These transgenic mice repres ent a useful model in which the fibroproliferative phase of connective tissue disease is uncoupled from inflammation.