Bradykinin induces matrix metalloproteinase-9 expression and cell migration through a PKC-delta-dependent ERK/Elk-1 pathway in astrocytes.
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.
Hsieh
Hsi-Lung
HL
Department of Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.
Wu
Cheng-Ying
CY
Yang
Chuen-Mao
CM
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D004791:Enzyme Inhibitors; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D001920:Bradykinin