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IL-1beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes.
Glia. 2009 Dec; 57(16):1775-89.GLIA

Abstract

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.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19455716

Citation

Wu, Cheng-Ying, et al. "IL-1beta Induces MMP-9 Expression Via a Ca2+-dependent CaMKII/JNK/c-JUN Cascade in Rat Brain Astrocytes." Glia, vol. 57, no. 16, 2009, pp. 1775-89.
Wu CY, Hsieh HL, Sun CC, et al. IL-1beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes. Glia. 2009;57(16):1775-89.
Wu, C. Y., Hsieh, H. L., Sun, C. C., & Yang, C. M. (2009). IL-1beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes. Glia, 57(16), 1775-89. https://doi.org/10.1002/glia.20890
Wu CY, et al. IL-1beta Induces MMP-9 Expression Via a Ca2+-dependent CaMKII/JNK/c-JUN Cascade in Rat Brain Astrocytes. Glia. 2009;57(16):1775-89. PubMed PMID: 19455716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-1beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes. AU - Wu,Cheng-Ying, AU - Hsieh,Hsi-Lung, AU - Sun,Chi-Chin, AU - Yang,Chuen-Mao, PY - 2009/5/21/entrez PY - 2009/5/21/pubmed PY - 2010/1/6/medline SP - 1775 EP - 89 JF - Glia JO - Glia VL - 57 IS - 16 N2 - 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. SN - 1098-1136 UR - https://www.unboundmedicine.com/medline/citation/19455716/IL_1beta_induces_MMP_9_expression_via_a_Ca2+_dependent_CaMKII/JNK/c_JUN_cascade_in_rat_brain_astrocytes_ DB - PRIME DP - Unbound Medicine ER -