ROLE OF SERUM AMYLOID-A AS AN INTERMEDIATE IN THE IL-1 AND PMA-STIMULATED SIGNALING PATHWAYS REGULATING EXPRESSION OF RABBIT FIBROBLAST COLLAGENASE

The matrix metalloproteinase collagenase is expressed by resident tiss ue cells only when needed for biological remodeling. Exogenous additio n of inflammatory and growth-promoting cytokines stimulates collagenas e expression in early passage fibroblast cultures, In addition, the si gnal for collagenase expression in response to phorbol-12-myristate-13 acetate (PMA) or to agents which alter cell shape in early passage fi broblast cultures is routed extracellularly to an autocrine cytokine i ntermediate, IL-1 alpha. Importantly, fibroblasts, when freshly isolat ed from the tissue, are not competent for IL-1 alpha gene expression a nd, therefore, cannot produce collagenase in response to shape change agents. However, they do make a small amount of collagenase in respons e to PMA via an IL-1-independent pathway that has not been further cha racterized. In this paper, we investigate the role of a second autocri ne, serum amyloid A3 (SAA3), in IL-1-dependent and -independent collag enase gene expression. We demonstrate that SAA3 is required for effect ive stimulation of collagenase expression by either exogenous or endog enous IL-1. Furthermore, while freshly isolated fibroblasts cannot exp ress IL-1 alpha they can express SAA3, and this autocrine mediator act s independently of IL-1 alpha to control the low level of collagenase expression that can be stimulated by PMA. These results provide furthe r evidence for a newly emerging paradigm of collagenase regulation whi ch emphasizes the requirement for extracellular routing of signals. Th ey also suggest that SAA3 might be utilized independently of IL-1 alph a to control tissue remodeling in vivo. (C) 1997 Academic Press.