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Bradykinin induces matrix metalloproteinase-9 expression and cell migration through a PKC-delta-dependent ERK/Elk-1 pathway in astrocytes.

Author	Hsi-Lung Hsieh, Cheng-Ying Wu, Chuen-Mao Yang
Citation Information	Glia, 56:619-32 (2008)
Keywords	Analysis of Variance, Animals, Astrocytes, Bradykinin, Brain, Cell Line, Transformed, Cell Movement, Dose-Response Relationship, Drug, Drug Interactions, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, Matrix Metalloproteinase 9, Protein Kinase C-delta, Rats, Signal Transduction, Time Factors
Related Products	06-866
Pub Med ID	18240315

Many reports have shown that matrix metalloproteinase (MMP)-9 plays an important role in brain inflammation and diseases. In our previous study, bradykinin (BK) has been shown to induce proMMP-9 expression via MAPKs and NF-kappaB in rat brain astrocytes (RBA-1). However, the molecular mechanisms and physiological roles underlying BK-induced MMP-9 expression in RBA-1 remain unclear. Here we reported that BK induced proMMP-9 expression and promoted RBA-1 cell migration, via a B(2) BK receptor-activated protein kinase C-delta (PKC-delta)-dependent signaling pathway. Activation of PKC-delta led to phosphorylation and translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) and then activated a transcription factor Elk-1. Phospho-Elk-1 bound to MMP-9 promoter and thereby induced transcription of MMP-9. The rat MMP-9 promoter containing an Elk-1 cis-binding site (Ets domain), that located at nucleotides -511 to -506 was identified as a crucial domain linking to BK action. Moreover, BK induced recruitment of p300 (as a transcriptional co-activator) to the MMP-9 promoter, leading to the acetylation of histone H4 in chromatin and facilitating MMP-9 gene transcription. Taken together, these results suggested that in RBA-1 cells, activation of ERK1/2 by a PKC-delta-dependent event mediated through Elk-1 pathway is essential for MMP-9 gene up-regulation and cell migration induced by BK.