ACTIVATION OF HUMAN MONOCYTES THROUGH CD40 INDUCES MATRIX METALLOPROTEINASES

The activation of monocytes/macrophages to secrete pro-inflammatory cy tokines and matrix metalloproteinases (MMPs) is critically important i n the development of chronic inflammatory diseases. However, the conse quence of interactions between activated T cells and monocytes in thes e 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 l ine, BMS-2, that expresses high levels of the CD40 ligand gp39 (also c alled TRAP, TBAM, or CD40L) stimulate both the expression of mRNA and the production of MMPs by human monocytic cells. Activation of monocyt es 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 meta lloproteinase(gelatinase) in both the human monocytic cell line, THP-1 , and peripheral human monocytes, and induction was blocked by the ant i-human gp39 Ab. Pretreatment with IFN-gamma significantly enhanced gp 39 induction of MMPs in THP-1 cells but not in peripheral monocytes. U p-regulation of mRNA for the 92-kDa MMP by gp39 could be detected with in 6 h of stimulation and was maximal 24 h after treatment. MMP enzyma tic activity was detectable in the culture medium 12 to 18 h following stimulation of the cells and remained high through 48 h. These result s suggest the interaction of T cells with monocytes/macrophages via th e gp39-CD40 counter receptors may be significant in development or mai ntenance of chronic inflammatory lesions.