Role of Enzyme Receptors and Inhibitors in Regulating Proteolytic Activities of Macrophagesa

Abstract

Expression of proteases by neutrophils and other cells with a prominent regulated secretory pathway is determined largely by stimulus-response secretion of proteins prepackaged in high concentration. The regulated secretory pathway is apparently minor in macrophages, and instead proteases are either channeled into lysosomes or secreted constitutively. Posttranslational regulation of macrophage proteases then depends on compartmentalizing enzymes to their sites of primary function. Available data suggest that cells use both specific receptors and inhibitors to accomplish this. Viewed in this context protease inhibitors primarily function to inhibit enzyme not bound to their receptor. Consonant with this model of regulation, connective tissue turnover by macrophages is a contact-dependent process relatively resistant to exogenous macromolecular inhibitors. Although limited information is available regarding determinants that modulate matrix metabolism by human macrophages, this model suggests that determinants of adhesion and colocalization of enzyme and substrate would be as or more important than alterations of inhibitors in the microenvironment of the cell.