An interleukin-1 loop is induced in human skin fibroblasts upon stress relaxation in a three-dimensional collagen gel but is not involved in the up-regulation of matrix metalloproteinase 1.
The integrin-mediated stress relaxation as it occurs in a retracting three-dimensional collagen gel (RCG) is accompanied by a large up-regulation of the interstitial collagenase, matrix metalloproteinase 1 ((MMP-1), EC 3.4.24.7), regulated notably by interleukin-1 (IL-1), phorbol esters, and cytoskeleton-disrupting drugs as cytochalasin D (CD). The repression of MMP-1 up-regulation in RCG by cycloheximide suggested the participation in the regulation process of a de novo synthesized intermediary component. We demonstrate here that culture of human skin fibroblasts in RCG or in CD- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated monolayers resulted in the activation of an IL-1 autocrine feedback loop that was switched off by the naturally occurring IL-1 receptor antagonist (IL-1RA), a blocker of the common IL-1 receptor. The IL-1RA did not suppress the MMP-1 up-regulation induced in RCG nor in CD-treated cells, indicating that the up-regulation of MMP-1 and the IL-1 autocrine loop occurred in an independent way, while the TPA-induced MMP-1 expression was suppressed by the receptor antagonist. The RCG- as well as the TPA-, IL-1-, and CD-induced up-regulation of both MMP-1 and IL-1 was totally suppressed by protein tyrosine kinases inhibitors. In contrast bisindoylmaleimide, at a concentration (5 microM) that inhibits the TPA-induced protein kinase C activity, suppressed the CD-induced MMP-1 expression but did not or barely altered that induced in RCG or by IL-1. None of the other tested inhibitors of a variety of signaling pathways including those used by integrins was able to suppress the RCG or CD-induced MMP-1. These results point to a potent regulation of MMP-1 by mechanical stress relaxation, a process depending on de novo protein synthesis and occurring independently of the activation of an IL-1 autocrine feedback loop.
Laboratory of Connective Tissues Biology, University of Liège, Tour de Pathologie B23/3, B-4000 Sart Tilman, Belgium.
C A
CA
Lambert
C M
CM
Lapiere
B V
BV
Nusgens
D002147:Calmodulin / Q000378:metabolism; D003094:Collagen; D017364:Collagenases; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015638:Cytochalasin D / Q000494:pharmacology; D005109:Extracellular Matrix; D005347:Fibroblasts / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D005782:Gels; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1; D008928:Mitochondria / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D002147:Calmodulin; D005782:Gels; D007375:Interleukin-1; D018078:Receptors, Prostaglandin E; D015638:Cytochalasin D; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate