The activation of monocytes/macrophages to secrete pro-inflammatory cytokines and matrix metalloproteinases (MMPs) is critically important in the development of chronic inflammatory diseases. However, the consequence of interactions between activated T cells and monocytes in these inflammatory processes is not well understood. In this study we have investigated the induction of MMPs in human monocytes by activated T cells. We show that fixed cells and the cell membranes from a T cell line, BMS-2, that expresses high levels of the CD40 ligand gp39 (also called TRAP, TBAM, or CD40L) stimulate both the expression of mRNA and the production of MMPs by human monocytic cells. Activation of monocytes by the human T cells could be significantly inhibited by a F(ab')2 fragment of a neutralizing Ab specific for human gp39, but not by an Ab that recognizes murine gp39. Furthermore, recombinant soluble gp39 (sgp39) alone induced marked increases in the levels of a 92-kDa metalloproteinase (gelatinase) in both the human monocytic cell line, THP-1, and peripheral human monocytes, and induction was blocked by the anti-human gp39 Ab. Pretreatment with IFN-gamma significantly enhanced gp39 induction of MMPs in THP-1 cells but not in peripheral monocytes. Up-regulation of mRNA for the 92-kDa MMP by gp39 could be detected within 6 h of stimulation and was maximal 24 h after treatment. MMP enzymatic activity was detectable in the culture medium 12 to 18 h following stimulation of the cells and remained high through 48 h. These results suggest the interaction of T cells with monocytes/macrophages via the gp39-CD40 counter receptors may be significant in development or maintenance of chronic inflammatory lesions.