Differential inhibition of collagenase and interleukin-1α gene expression in cultured corneal fibroblasts by TGF-β, dexamethasone, and retinoic acid

PURPOSE. Expression of the genes for collagenase and interleukin-1α (IL-1α) are induced as stromal cells become activated to the repair fibroblast phenotype after injury to the cornea. This investigation examines the mechanisms whereby expression of these genes is inhibited by transforming growth factor-β (TGF-β), dexamethasone (DEX), or retinoic acid (RET A). METHODS. A model of freshly isolated cultures of corneal stromal cells and early passage cultures of corneal fibroblasts was used in these studies. This model reproduces the events of stromal cell activation in the corneal wound. RESULTS. In early passage cultures of corneal fibroblasts, expression of collagenase is under obligatory control by autocrine IL-1α. IL-1α controls its own expression through an autocrine feedback loop that is dependent on transcription factor NF-κB. TGF-β, DEX, and RET A were each effective inhibitors of collagenase gene expression in these cells. Furthermore, these agents have the capacity to inhibit expression of IL-1α and this was correlated with their ability to affect DNA-binding activity of NF-κB. However, TGF-β, DEX, and RET A were also effective inhibitors of the low level of collagenase expressed by freshly isolated corneal stromal cells that cannot express IL-1α. CONCLUSIONS. In cells with an active IL-1α autocrine loop there are at least two distinct signaling pathways by which collagenase gene expression can be modulated. The results of this study demonstrate that TGF-β, DEX, and RET A differentially inhibit collagenase and IL-1α gene expression. This information will be useful in the design of therapeutic modalities for fibrotic disease in the cornea and other parts of the eye.