HUMAN B-LYMPHOCYTES SYNTHESIZE THE 92-KDA GELATINASE, MATRIX METALLOPROTEINASE-9

Matrix metalloproteinases (MMPs) are involved in the remodeling of con nective tissue as well as in disease states associated with acute and chronic inflammation or tumoral metastatic processes. Despite detailed and extensive studies of the mechanisms of lymphocyte extravasation, remarkably little is known about the expression and regulation of meta lloproteinases involved in the migratory process. By using zymography and reverse transcription-polymerase chain reaction experiments, we ha ve demonstrated that Epstein-Barr virus-immortalized B lymphocytes are able to secrete a 92-kDa metalloproteinase with gelatinolytic activit y which has been purified and identified as being MMP-9. Moreover, the tissue inhibitor of metalloproteinase was shown to be constitutively expressed by the B cells. The expression of 92-kDa gelatinase is media ted by cytokines, growth factors, lipopolysaccharide, concanavalin A, and the tumor promotor phorbol 12-myristate 13-acetate. Time dependenc e activity increased rapidly up to 24 h of incubation with lipopolysac charide or concanavalin A stimulation while it requires a delay and mo re time to have an optimum effect when cytokines were the stimulating agents; transforming growth factor-p abolished 92-kDa gelatinase produ ction. Both staurosporine and wortmannin are inductive stimuli, and th e level of MMP-9 secreted into the media is greater than that observed with other agents except concanavalin A. Elicitation of the chemotact ic migration of B cells through a model basement membrane by lipopolys accharide was shown to be correlated with gelatinase expression and in hibited by 7 mM captopril. Our study indicates that Epstein-Barr virus -B lymphocytes express 92-kDa gelatinase, the production of which can be modified by a variety of physiological and pharmacological signals which have been shown to differ according to the cell type.