MODULATION OF TRANSFORMING GROWTH-FACTOR-BETA-1 STIMULATED ELASTIN AND COLLAGEN PRODUCTION AND PROLIFERATION IN PORCINE VASCULAR SMOOTH-MUSCLE CELLS AND SKIN FIBROBLASTS BY BASIC FIBROBLAST GROWTH-FACTOR, TRANSFORMING GROWTH FACTOR-ALPHA, AND INSULIN-LIKE GROWTH FACTOR-I

During tissue repair and development, matrix accumulation is modulated as multiple signals impinge on target cells. We have investigated the effects of combinations of the mitogenic cytokines, basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGF-alpha), and insulin-like growth factor-1 (IGF-1) with transforming growth factor-beta 1 (TGF-beta1) with respect to the production of two matrix components, elastin and type I collagen. Using specific enzyme-linked immunoassays for detection of secreted precursors in both vascular smooth muscle cells and skin fibroblasts from the domestic pig, production of these two fibrous proteins was shown to be strongly stimulated by TGF-beta1. In the smooth muscle cell, both bFGF and TGF-alpha were potent antagonists of TGF-beta1-mediated matrix production, whereas IGF-1 was only weakly additive with respect to elastin production. Antagonism was also evident to a lesser extent in skin fibroblasts. Reduced responsiveness to TGF-beta1 did not appear to be due to a switch to a proliferative state, since TGF-beta1 itself acted as a mitogen in confluent SMC, and TGF-alpha was only a weak mitogen in confluent fibroblast cultures. Although a predominant effect of TGF-beta is matrix accumulation, these findings suggest that this property will be significantly modified by the cytokine context.