Regulation of the levels of human trabecular matrix metalloproteinases and inhibitor by interleukin-1 and dexamethasone

The regulation of the trabecular meshwork's extracellular matrix is poorly understood and may involve a family of secreted proteinases, the matrix metalloproteinases. Because the trabecular extracellular matrix has been hypothesized to affect intraocular pressure, an evaluation was made of the ability of two cellular modulators to change the levels of matrix metalloproteinases in the medium of human trabecular meshwork organ explant cultures. Trabecular explant cultures were exposed to recombinant human interleukin-1 alpha, dexamethasone, or combinations thereof for 72 hours and the culture medium was collected for analysis. Levels of stromelysin, the 72 kD gelatinase A and the 92 kD gelatinase B enzyme activity in this culture medium were assayed by substrate gel electrophoresis (zymography). Stromelysin and the tissue inhibitor of metalloproteinases (TIMP1) media protein levels were analyzed using immunoblots of Western transfers. Culture medium of unstimulated explants contains significant levels of the 72 kD gelatinase A and only low levels of the 92 kD gelatinase B, stromelysin, and TIMP1. Interleukin-1 alpha produces a dose-dependent several-fold elevation of gelatinase B, stromelysin, and TIMP1 without changing gelatinase A levels. Dexamethasone produces no significant change in gelatinase A and only small increases in stromelysin, gelatinase B, and TIMP1. When added together, dexamethasone antagonizes the interleukin-1 alpha-induced increase of stromelysin, gelatinase B, and TIMP1 in a dose-dependent manner. These modulators may be useful in analyzing the roles of this enzyme family in normal trabecular homeostasis and perhaps in the etiology of glaucoma.