Document Detail

IL-1beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes.
MedLine Citation:
PMID:  19455716     Owner:  NLM     Status:  MEDLINE    
Interleukin (IL)-1beta has been shown to induce matrix metalloproteinase (MMP)-9 expression through mitogen-activated protein kinases, including JNK, in rat brain astrocyte-1 (RBA-1) cells. However, little is known about whether JNK activated by Ca(2+)-dependent CaMKII is associated with MMP-9 expression induced by IL-1beta. Here, we report that the Ca(2+)/CaMKII/JNK/c-Jun participates in the MMP-9 expression induced by IL-1beta. Zymographic, Western blotting, and RT-PCR analyses showed that IL-1beta-induced expression of MMP-9 mRNA and protein was attenuated by Ca(2+) chelator (BAPTA), and the inhibitors of ER Ca(2+)-ATPase (thapsigargin), CaMKII (KN-62), and JNK1/2 (SP600125). IL-1beta also stimulated phosphorylation of CaMKII and JNK1/2, and increase in intracellular Ca(2+) ([Ca(2+)](i)), which were inhibited by pretreatment with BAPTA, thapsigargin (TG), KN-62, or SP600125. Furthermore, the upregulation of MMP-9 protein was blocked by transfection with c-Jun or CaMKII short hairpin RNA (shRNA). We further confirmed that IL-1beta stimulated c-Jun associated with AP-1-binding sites within MMP-9 promoter (-87 to -80 bp and -511 to -497 bp) by immunoprecipitation and chromatin immunoprecipitation (ChIP)-PCR assays. The activation and recruitment of c-Jun to MMP-9 promoter were inhibited by pretreatment with BAPTA, TG, KN-62, or SP600125. Moreover, IL-1beta-induced MMP-9 gene transcription by AP-1 was confirmed by transfection with a MMP-9 promoter-luciferase reporter plasmid with a distal AP-1-binding site (-511 to -497 bp) adjacent to an Ets-binding site-mutation (mt-AP1/Ets-MMP-9). These results demonstrated that in RBA-1 cells, JNK/c-Jun activation was mediated through a Ca(2+)-dependent CaMKII pathway that promoted transcription factor c-Jun/AP-1 recruitment and eventually led to increase in MMP-9 expression by IL-1beta.
Cheng-Ying Wu; Hsi-Lung Hsieh; Chi-Chin Sun; Chuen-Mao Yang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Glia     Volume:  57     ISSN:  1098-1136     ISO Abbreviation:  Glia     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-10-20     Completed Date:  2010-01-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8806785     Medline TA:  Glia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1775-89     Citation Subset:  IM    
Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
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MeSH Terms
Analysis of Variance
Astrocytes / drug effects,  metabolism*
Blotting, Western
Brain / drug effects,  metabolism*
Calcium / metabolism*
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
Cell Line
Chromatin Immunoprecipitation
Electrophoresis, Gel, Two-Dimensional
Electrophoretic Mobility Shift Assay
Enzyme Inhibitors / pharmacology
Interleukin-1beta / metabolism,  pharmacology*
JNK Mitogen-Activated Protein Kinases / metabolism*
Matrix Metalloproteinase 9 / genetics,  metabolism*
Promoter Regions, Genetic
Proto-Oncogene Proteins c-jun / metabolism*
RNA, Messenger / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects,  physiology
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Interleukin-1beta; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 7440-70-2/Calcium; EC Protein Kinase Type 2; EC Mitogen-Activated Protein Kinases; EC Metalloproteinase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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