Cooperation between SMAD and NF-κB in growth factor regulated type VII collagen gene expression

Abstract

We have previously demonstrated that transforming growth factor-β (TGF-β) and pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin-1β, synergistically enhance the expression of type VII collagen gene (COL7A1) in human dermal fibroblasts in culture (Mauviel et al., 1994). Recently, we identified a SMAD-containing complex, rapidly induced by TGF-β and binding the region [−496/−444] of the COL7A1 promoter, responsible for COL7A1 gene transactivation (Vindevoghel et al., 1998a). In this report, we demonstrate that TGF-β and TNF-α response elements are distinct entities within the COL7A1 promoter. In particular, we demonstrate that the TNF-α effect is mediated by NF-κB1/RelA (p50/p65) and RelA/RelA (p65/p65) NF-κB complexes binding the TNF-α response element (TaRE) located in the region [−252/−230], with RelA acting as the transcriptional activator. Finally, we provide definitive evidence for the role of both TGF-β and TNF-α response elements as enhancer sequences, functioning in the context of a heterologous promoter in an additive manner in response to TGF-β and TNF-α. This study provides the first identification of a functional interaction between the two immediate-early transcription factors, SMAD and NF-κB, to activate the expression of an extracellular matrix-related gene, COL7A1.