This project focusses on the biochemical events involved in the PGE2-cAMP dependent signal transduction in the monocyte that leads to the production of metalloproteinases. This last year the emphasis of this research has been on the mechanisms by which cytokines regulate the events involved in this pathway. Of particular interest is the effect of cytokines on the recently described inducible form of prostaglandin synthase known as prostaglandin H synthase-2 (PGHS-2). Preincubation of monocytes with interleukin-4 (IL-4) caused a significant suppression of Con A induced PGHS-2 as demonstrated at the mRNA and membrane protein level. This appears to be the primary mechanism by which IL-4 inhibits the production of PGE2 and the subsequent production of metalloproteinases since phospholipase activity, as assessed by HPLC analysis, appears to be relatively unaffected by IL-4. Interleukin-10 is another cytokine, that as a result of its suppression of mRNA and membrane protein levels of PGHS-2, was found to inhibit matrix metalloproteinase synthesis by monocytes. In contrast to IL-4 and IL-10, transforming growth factor beta (TGFbeta) was shown to enhance the induction of PGHS-2 mRNA and protein by Con A. The ability of TGFbeta to enhance PGHS-2 was also reflected in increased production of prostaglandins, including PGE2. While TGFbeta enhanced monocyte eicosanoid synthesis, matrix metalloproteinase was not consistently increased by TGFbeta, indicating that this cytokine may be affecting additional signalling events in this pathway.
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