Macrophage proteases and rheumatic diseases: Regulation of plasminogen activator by thymus-derived lymphocytes

Macrophages in culture secrete a variety of products including neutral protease activities such as plasminogen activator(s) (P.A.), collagenase and elastase. These products are not made by unstimulated macrophages, but only after induction by inflammatory stimuli, phagocytosis and lymphokines. Phagocytosis induces the prompt release of high levels of P.A. by endotoxin-primed macrophages and prolonged secretion follows uptake of non-degradable particles. Stimulation of lymphocytes results in the release of a supernatant product which enhances P.A. secretion by unstimulated mouse macrophages up to 5-fold. The production of the P.A. inducer (P.A.I.) is immunologically specific and is found in allogeneic mixed leukocyte culture (MLC) reactions, but not in syngeneic controls. The P.A. is also induced in activated macrophages from animals infected with BCG orT. cruzi and challenged with specific antigen. Production of the P.A.I. in MLC reactions depends on the presence of thymus-derived (T) lymphocytes and is closely correlated with the appearance of macrophage migration inhibition factor (MIF).The induction of macrophage P.A. and other proteases provides an important pathway for activating macrophages in delayed hypersensitivity reactions and could contribute significantly to tissue destruction in chronic inflammatory diseases in joints.