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

FEBS Letters

Fabunmi, Rosalind P¹  Newby, Andrew C¹  Baker, Andrew H¹  Bond, Mark¹ 

[1] Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK

关键词: Metalloproteinase;    Nuclear factor kappa-B;    Extracellular matrix;    Fibroblast;    bFGF;    basic fibroblast growth factor;    BM;    basement membrane;    GAPDH;    glyceraldehyde-3-phosphate dehydrogenase;    IL-1α;    interleukin-1α;    MMP;    metalloproteinase;    PMA;    phorbol myristate acetate;    PDGF;    platelet-derived growth factor;    RAd;    recombinant adenovirus;    TNF-α;    tumour necrosis factor-α;   

DOI  :  10.1016/S0014-5793(98)01034-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown