This project focusses on the biochemical pathways involved in signal transduction in the monocyte. Our recent studies have examined the role of guanine nucleotide binding proteins (G proteins) in the prostaglandin- cyclic AMP dependent pathway of collagenase production by monocytes. Previous findings from these studies have demonstrated that stimulation of monocytes with Con A activates the 46-kDa Gsalpha protein as demonstrated by its ribosylation. Activation of the Gsalpha protein correlates with increases in products generated from the prostaglandin synthetase (cyclooxygenase) pathway. Immunoprecipitation studies with antibodies against either prostaglandin synthetase or Gsalpha revealed that stimulation with Con A induced a coupling between Gsalpha and prostaglandin synthetase which results in activation of both proteins. Thus, this is the first demonstration of a G protein coupled to prostaglandin synthetase and explains the mechanism by which G proteins elevate PGE2 and as a result enhance collagenase production. In additional studies, we have examined the effect of cytokines on the production of interstitial and type IV collagenase. IL-4, which has previously been shown to inhibit PGE2, inhibited membrane associated prostaglandin synthetase. The inhibition of PGE2 by IL-4 resulted in the suppression of both interstitial and the 92- kDa type IV monocyte collagenase as demonstrated by the restoration of these enzymes with exogenous PGE2 or dBcAMP. Furthermore the 92-kDa type IV collagenase could also be inhibited by indomethacin, indicating the production of this enzyme is, like interstitial collagenase, PGE2-cAMP dependent. Studies with TGFbeta have shown that, in contrast to IL-4, it enhances Con A-induced prostaglandin synthetase metabolites including PGE2. Moreover, TGFbeta also enhances interstitial and the 92-kDa type IV collagenase.
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