COMPETENCE FOR COLLAGENASE GENE-EXPRESSION BY TISSUE FIBROBLASTS REQUIRES ACTIVATION OF AN INTERLEUKIN-1-ALPHA AUTOCRINE LOOP

The enzyme collagenase (EC 3.4.24.7), a key mediator in biological rem odeling, can be induced in early-passage fibroblasts by a wide variety of agents and conditions. In contrast, at least some primary tissue f ibroblasts are incompetent to synthesize collagenase in response to ma ny of these stimulators. In this study, we investigate mechanisms cont rolling response to two of the conditions in question: (i) trypsin or cytochalasin B, which disrupt actin stress fibers, or (ii) phorbol 12- myristate 13-acetate (PMA), which activates growth factor signaling pa thways. We demonstrate that collagenase expression stimulated by tryps in or cytochalasin B is regulated entirely through an autocrine cytoki ne, interleukin 1 alpha (IL-1 alpha). The IL-1 alpha intermediate also constitutes the major mechanism by which PMA stimulates collagenase e xpression, although a second signaling pathway(s) contributes to a min or extent. Elevation of the IL-1 alpha level in response to stimulator s is found to be sustained by means of an autocrine feedback loop in e arly-passage fibroblast cultures. In contrast, fibroblasts freshly iso lated from the tissue are incompetent to activate and sustain the IL-1 alpha feedback loop, even though they synthesize collagenase in respo nse to exogenous IL-1. We conclude that this is the reason why tissue fibroblasts are limited, in comparison with subcultured fibroblasts, i n their capacity to synthesize collagenase. Activation of the IL-1 alp ha feedback loop, therefore, seems likely to be an important mechanism by which resident tissue cells adopt the remodeling phenotype.