Identification of TIMP-2 in human alveolar macrophages. Regulation of biosynthesis is opposite to that of metalloproteinases and TIMP-1.

We have identified the metalloproteinase inhibitor TIMP-2 as a secreted product of human alveolar macrophages. In contrast to human fibroblasts, TIMP-2 was released from macrophages free of any apparent complexed metalloproteinases. Also in marked distinction to fibroblasts, TIMP-2 secretion from mononuclear phagocytes was subject to modulation by a variety of agents. TIMP-2 was synthesized by macrophages placed in culture under basal conditions in amounts approximately 30% of those secreted by fibroblasts on a per cell basis. The additions of lipopolysaccharide, denatured type I collagen, and zymosan to culture medium each resulted in a dose-dependent and profound decrease in macrophage TIMP-2 protein production and steady-state mRNA levels. In contrast, all of these agents markedly enhanced the biosynthesis of macrophage interstitial collagenase and TIMP-1 as assessed by analysis of identical cell and conditioned media samples. In human fibroblasts, TIMP-2 biosynthesis was unaffected by interleukin-1, tumor necrosis factor-alpha, platelet-derived growth factor, and phorbol ester despite the massive collagenase stimulation induced by each of these agents. We conclude that TIMP-2 is a potentially important mononuclear phagocyte product whose biosynthesis is regulated in a distinct and completely opposite manner to that of collagenase and TIMP-1.