DIFFERENTIAL REGULATION OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS IN HUMAN GLOMERULAR EPITHELIAL-CELLS IN-VITRO

The present study examines the effect of transforming growth factor-be ta(1) (TGF-beta(1)) and interleukin-1 beta (IL-1 beta) on the regulati on of gelatinase A, gelatinase B, tissue inhibitor of metalloproteinas e-I (TIMP-I) and TIMP-II in human glomerular epithelial cells (GEC). T he addition of TGF-P, resulted in the increased production and secreti on of both gelatinase A (72-kD type IV collagenase) and gelatinase B ( 92-kD type IV collagenase), in a dose- and time-dependent manner. In c ontrast, the addition of IL-1 beta to GEC resulted in the stimulation of secretion of gelatinase B but not gelatinase A. When the secretion of the regulatory inhibitors was examined, IL-1 beta or TGF-P, both re sulted in an increased secretion of TIMP-I, whereas the secretion of T IMP-II was downregulated. Such results demonstrate an independent and opposite regulation of the enzymes and their inhibitors. Of particular interest was the observation of the differential regulation of gelati nase A and its specific inhibitor TIMP-II (which binds to the latent f orm of this enzyme) in response to TGF-P,. These results for the first time indicate that in human GEC, matrix metalloproteinases (MMP), as well as their specific inhibitors, are independently regulated by diff erent cytokines. MMP and their regulatory tissue inhibitors (TIMP) pla y an important role in tissue remodeling. The results of the present s tudy serve to emphasize both the complex regulation of matrix metaboli sm in the glomerulus and the potential pathologic role of an imbalance between the proteinases and their inhibitors in various forms of glom erular disease.