Transforming growth factor-beta and interleukin-1 modulate metalloproteinase expression by corneal stromal cells

Abstract

The enzyme collagenase participates in remodeling the extracellular matrix of corneal stroma during normal wound healing and mediates the degradation of extracellular matrix that occurs in many corneal pathologic states. Because this enzyme is synthesized and secreted by corneal cells, therapy of degradative disorders might be geared toward control of enzyme expression. The effects of two cytokines, transforming growth factor-beta (TGF-beta) and interleukin-1 (IL-1), on the expression of collagenase by cultured corneal stromal cells are reported. In addition, the concomitant effects of these cytokines on expression of three additional members of the matrix metalloproteinase (MMP) family--stromelysin, 72-kilodalton (kD) gelatinase, and 92-kD gelatinase--were investigated. When stromal cells are situated in the normal corneal stroma, they produce only a single MMP, 72-kD gelatinase. This pattern of expression was reproduced by stromal cells freshly plated in primary culture. However after passage in culture, the cells also began to secrete collagenase and stromelysin. Treatment of primary cultures with recombinant human IL-1 also induced collagenase and stromelysin expression. In addition, 92-kD gelatinase expression was induced and 72-kD gelatinase expression was increased further by IL-1 treatment. Treatment of passaged cultures or IL-1-treated primary cultures with recombinant human TGF-beta reverted the pattern of enzyme expression toward that exhibited by primary, untreated cultures, ie, expression of collagenase and stromelysin was repressed while expression of 72-kD gelatinase was increased. These results suggest that TGF-beta and IL-1 may be important agents for controlling MMP expression in healthy and diseased corneas.