Abstract
Transforming growth factor-beta (TGF-beta) plays a major role in regulating connective tissue deposition by controlling both extracellular matrix production and degradation. In this study, we show that TGF-beta transcriptionally represses both basal and tumor necrosis factor-alpha-induced collagenase (matrix metalloprotease-1) gene expression in dermal fibroblasts in culture, whereas it activates its expression in epidermal keratinocytes. We demonstrate that this differential effect of TGF-beta on collagenase gene expression is due to a cell type-specific induction of distinct oncogenes of the Jun family, which participate in the formation of AP-1 complexes with different trans-activating properties. Specifically, our data indicate that the inhibitory effect of TGF-beta in fibroblasts is likely to be mediated by jun-B, based on the following observations: (a) TGF-beta induces high levels of jun-B expression and (b) over-expression of jun-B mimics TGF-beta effect in inhibiting basal collagenase promoter activity and preventing tumor necrosis factor-alpha-induced trans-activation of the collagenase promoter. In contrast, TGF-beta induction of collagenase gene expression in keratinocytes is preceded by transient elevation of c-jun proto-oncogene expression. Over-expression of c-jun leads to trans-activation of the collagenase promoter in both cell types, suggesting that c-jun is a ubiquitous inducer of collagenase gene expression. Transfection of keratinocytes with an antisense c-jun construct together with a collagenase promoter/reporter gene construct inhibits basal and TGF-beta-induced up-regulation of the collagenase promoter activity, implying that c-jun mediates TGF-beta effect in this cell type. Collectively, our data suggest differential signaling pathways for TGF-beta in dermal fibroblasts and epidermal keratinocytes, leading to cell type-specific induction of two AP-1 components with opposite transcriptional activities.
Highlights
Matrix metalloproteases comprise a family of proteolytic enzymes involved in the degradation of the extracellular matrix of connective tissue
We show that TGF- transcriptionally represses both basal and tumor necrosis factor␣-induced collagenase gene expression in dermal fibroblasts in culture, whereas it activates its expression in epidermal keratinocytes
We demonstrate that this differential effect of TGF- on collagenase gene expression is due to a cell type-specific induction of distinct oncogenes of the Jun family, which participate in the formation of AP-1 complexes with different trans-activating properties
Summary
Matrix metalloproteases comprise a family of proteolytic enzymes involved in the degradation of the extracellular matrix of connective tissue (for reviews see Refs. 1 and 2). Recent in vivo observations have revealed that during cutaneous wound healing, the expression of collagenase is very low in the dermis, whereas it is markedly elevated in basal keratinocytes at the wound edges [5]. In this context, the close topographic proximity of fibroblasts and keratinocytes led us to investigate in vitro the signals that would be responsible for the differential, cell type-specific expression of collagenase during wound healing. We demonstrate that cell-specific induction of different oncogenes of the Jun family, with opposite trans-activating properties, is responsible for the differential regulation of collagenase gene expression by TGF- in fibroblasts and keratinocytes
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