Inhibition by Interleukin-4 of stromelysin expression in human skin fibroblasts: role of PKC.
This study explores novel aspects of the interaction between inflammatory mediators and extracellular matrix degradation. Here we have evaluated the effects of a T-cell cytokine interleukin-4 (IL-4) on the expression and activity of a metalloprotease, stromelysin, and its tissue inhibitor (TIMP-1) in human skin fibroblasts. IL-4 strongly decreased stromelysin mRNA levels and stromelysin-producing activity induced by IL-1 beta-treated and untreated cells. Under the same experimental conditions, TIMP-1 mRNA expression was slightly modified. Phorbol ester (PMA), a PKC activator, induced stromelysin gene expression, an effect enhanced by the addition of IL-1 beta. IL-4 was not able to decrease the PMA and PMA + IL1 beta effects. Calphostin, a specific PKC inhibitor, inhibited stromelysin mRNA expression induced by IL-1 beta. Forskolin, a PKA activator, did not modify mRNA levels and was not able to reduce the effect of IL-4 on IL-1 beta-induced stromelysin expression. These data suggest that in human dermal fibroblasts, activation of PKC abolishes the observed IL-4 effect on both basal and IL-1 beta-induced stromelysin gene expression. It therefore appears that lack of PKC activation is a prerequisite for the inhibitory effect of IL-4 in the system.
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Istituto di Ricerche Farmacologiche Mario Negri, Italy.
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Rotilio
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D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology; D011480:Protease Inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases
D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007375:Interleukin-1; D009281:Naphthalenes; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; C058747:calphostin A; D015847:Interleukin-4; D011493:Protein Kinase C; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D013755:Tetradecanoylphorbol Acetate