This project focusses on the biochemical pathways involved in signal transduction in the monocyte that lead to the production of metalloproteinases. Our previous studies have demonstrated that the production of these enzymes occurs through a a PGE2-cAMP dependent pathway involving G proteins. These studies demonstrated a potential coupling between prostaglandin synthetase (PGS) and a 46-kDa Gsalpha G protein that is ribosylated only in activated monocytes. Our recent findings have shown that the Con A induced ADP-ribosylation of the 46- kDa Gsalpha is suppressed by PGS inhibitors such as indomethacin and aspirin. This finding, along with the ability of cholera toxin (CT) to enhance prostaglandin synthesis only in Con A stimulated monocytes, indicates that the stimulant induced coupling between PGS and the 46-kDA GSalpha is required for the activation of the 46-kDa Gsalpha. Studies on PGS have revealed that a constitutive level of PGS-1 is expressed in the membranes of control monocytes. However, stimulation with Con A or LPS results in the induction of an inducible form of PGS (PGS-2). Moreover, the level of PGS-2 in stimulated monocytes is significantly enhanced by CT or TGFbeta. Thus, the ability of CT or TGF-beta to enhance prostaglandin production and, as a result, metalloproteinase production is due, in part, to the elevation of PGS-2 by these agents. Additionally, the suppression of PGS-2 by PT is most likely related to the inhibition of prostagladins and metalloproteinases by this toxin. Similarly, the ability of IL-4 to significantly inhibit the production of PGS-2 may explain the potent ability of this cytokine to suppress PGE2 production that results in the inhibition of metalloproteinases production.
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