INVOLVEMENT OF PROTEIN-KINASE-C IN THE INTERLEUKIN-1 ALPHA-INDUCED GENE-EXPRESSION OF MATRIX METALLOPROTEINASES AND TISSUE INHIBITOR-1 OF METALLOPROTEINASES (TIMP-1) IN HUMAN UTERINE CERVICAL FIBROBLASTS

The role of protein kinase C in the interleukin 1 (IL-1)-mediated prod uction of pro-matrix metalloproteinases (proMMPs) and tissue inhibitor -1 of metalloproteinases (TIMP-1) in human uterine cervical fibro-blas ts has been investigated. IL-1 and a protein kinase C activator, 12-O- tetradecanoylphorbol 13-acetate (TPA) augmented the production of proM MP-1 (interstitial procollagenase), proMMP-3 (prostromelysin-1) and TI MP-1, but their effects were inhibited by the protein kinase C inhibit ors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7 ) and staurosporine in a dose-dependent manner. The suppressive effect of H-7 and staurosporine on the IL-1-induced production of proMMPs-1 and -3 and TIMP-1 resulted from the decrease in the steady-state level s of their mRNAs. When protein kinase C was down-regulated by treating the cells with a high level of TPA, the inductive effect of IL-1 upon proMMP-3 production was reduced considerably. These results indicate that protein kinase C mediates the IL-1-induced production of proMMPs- 1 and -3 and TIMP-1 at the pretranslational level in human uterine cer vical fibroblasts. On the other hand, neither IL-1 nor TPA modulated t he production of proMMP-2 (progelatinase A). Both IL-1 and TPA also ac celerated the production of prostaglandin E2 (PGE2) by cervical fibrob lasts. However, the treatment of the cells with staurosporine in the p resence of IL-1 or TPA further augmented PGE2 synthesis, suggesting th at the increased synthesis of PGE2 by IL-1 treatment is mediated via s ignalling pathways distinct from those of proMMPs-1 and -3 and TIMP-1.