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Loop1
Department of Dermatology, University of Cologne, Cologne, Germany
Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C
chemokine superfamily, has recently been shown to be involved in the
pathogenesis of tissue fibrosis. In vitro studies demonstrated that
MCP-1 up-regulates type I collagen gene expression via endogenous
production of TGF-ß in rat lung fibroblasts. We here show that
recombinant human MCP-1 affects gene expression of interstitial
collagenase (matrix metalloproteinase-1 (MMP-1)) in primary human skin
fibroblasts and a stable fibroblast cell line. MMP-1 mRNA was induced
by MCP-1 (10 ng/ml) as early as 6 h and reached a maximal
expression at 24 h. MCP-1 also caused an increase of MMP-2 mRNA
expression in both types of fibroblasts at 48 h. Interestingly,
tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA was also
up-regulated by MCP-1, and TIMP-1 mRNA expression peaked at 48 h
in both types of fibroblasts. Immunoblot analysis demonstrated
increased levels of MMP-1 and TIMP-1 protein in the culture
supernatants of primary fibroblasts stimulated with MCP-1. In addition,
MCP-1 strongly induced IL-1
mRNA expression in dermal fibroblasts in
parallel with the induction of MMP-1. Preincubation with IL-1 receptor
antagonist almost completely abrogated the expression of MMP-1 mRNA,
and partially inhibited MMP-1 synthesis induced by MCP-1. Transient
transfection of primary skin fibroblasts with a MMP-1 promoter-reporter
construct indicated a dose-dependent increase in promoter activity by
MCP-1 stimulation. These data demonstrate that MCP-1 up-regulates MMP-1
mRNA expression and synthesis in human skin fibroblasts at a
transcriptional level and provide evidence that this is mediated by an
IL-1 autocrine loop.
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