Synergistic upregulation of metalloproteinase‐9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF‐κB

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Abstract
Matrix metalloproteinase (MMPs) enzymes are implicated in matrix remodelling during proliferative inflammatory processes including wound healing. We report here synergistic upregulation of MMP‐9 protein and mRNA by platelet‐derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) in combination with interleukin‐1α (IL‐1α) or tumour necrosis factor‐α (TNF‐α) in primary rabbit and human dermal fibroblasts. The synergistic interaction between growth factors and cytokines implies that basement membrane remodelling is maximal physiologically when both are present together. The signalling pathways mediating this synergistic regulation are not understood, although analysis of the MMP‐9 promoter has identified an essential proximal AP‐1 element and an upstream nuclear factor kappa‐B (NF‐κB) site. Using electromobility shift assays, binding to the AP‐1 site was only slightly increased by growth factors and cytokines. NF‐κB binding was rapidly induced by IL‐1α or TNF‐α but was neither induced nor potentiated by bFGF or PDGF. Neither AP‐1 nor NF‐κB was therefore sufficient on its own for synergistic regulation. Using a recently developed adenovirus that overexpresses the inhibitory subunit, IκBα, we demonstrated an absolute requirement for NF‐κB in upregulation of MMP‐9. Activation of NF‐κB binding by inflammatory cytokines was therefore necessary but not sufficient for synergistic upregulation of MMP‐9.