QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 6, 2005, 25(14):3701-3711; doi:10.1523/JNEUROSCI.4346-04.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (37) Citing Articles via Google Scholar Google Scholar Articles by Kim, Y. S. Articles by Joh, T. H. Search for Related Content PubMed PubMed Citation Articles by Kim, Y. S. Articles by Joh, T. H.

 Previous Article  |  Next Article 

Cellular/Molecular
Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia

Yoon Seong Kim,^1,2 Sung Soo Kim,¹ Jeong Je Cho,¹ Dong Hee Choi,^1,3 Onyou Hwang,³ Dong Hoon Shin,¹ Hong Sung Chun,⁴ M. Flint Beal,² and Tong H. Joh^1,2

¹Burke Medical Research Institute and ²Department of Neurology and Neuroscience, Weill Medical College and Graduate School of Medical Sciences of Cornell University, White Plains, New York 10605, ³Department of Biochemistry, Ulsan University School of Medicine, Seoul 138-736, South Korea, and ⁴Department of Genetic Engineering and Research Center for Proteineous Materials, Chosun University, Gwangju 501-759, South Korea

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders. We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration. We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12 cells and other media of apoptotic neuronal cells within 2-6 h of treatment of the cells, and SDM and catalytic domain of recombinant MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and cMMP-3 induced generation of tumor necrosis factor (TNF-), interleukin-6 (IL-6), IL-1, and interleukin-1 receptor antagonist but not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor anti-inflammatory cytokines, such as IL-10 and transforming growth factor-1, were induced. SDM and cMMP-3 extensively released TNF- from microglia and activated the nuclear factor-B pathway, and these microglial responses were totally abolished by preincubation with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12 cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a major role in degenerative human brain disorders, such as Parkinson's disease.

Key words: microglia; apoptosis; neurodegeneration; cytokines; matrix metalloproteinase-3; MMP-3

---

Received Oct 20, 2004; revised February 25, 2005; accepted February 25, 2005.

This article has been cited by other articles:

				X. Hu, D. Zhang, H. Pang, W. M. Caudle, Y. Li, H. Gao, Y. Liu, L. Qian, B. Wilson, D. A. Di Monte, et al. Macrophage Antigen Complex-1 Mediates Reactive Microgliosis and Progressive Dopaminergic Neurodegeneration in the MPTP Model of Parkinson's Disease J. Immunol., November 15, 2008; 181(10): 7194 - 7204. [Abstract] [Full Text] [PDF]

				T. Kawamura, K. Murakami, H. Bujo, H. Unoki, M. Jiang, T. Nakayama, and Y. Saito Matrix Metalloproteinase-3 Enhances the Free Fatty Acids-Induced VEGF Expression in Adipocytes Through Toll-Like Receptor 2 Experimental Biology and Medicine, October 1, 2008; 233(10): 1213 - 1221. [Abstract] [Full Text] [PDF]

				M. Xue, Y. Fan, S. Liu, D. A. Zygun, A. Demchuk, and V. W. Yong Contributions of multiple proteases to neurotoxicity in a mouse model of intracerebral haemorrhage Brain, September 4, 2008; (2008) awn215v1. [Abstract] [Full Text] [PDF]

				F. Ploger, P. Seemann, M. Schmidt-von Kegler, K. Lehmann, J. Seidel, K. W. Kjaer, J. Pohl, and S. Mundlos Brachydactyly type A2 associated with a defect in proGDF5 processing Hum. Mol. Genet., May 1, 2008; 17(9): 1222 - 1233. [Abstract] [Full Text] [PDF]

				R. Milner, S. J. Crocker, S. Hung, X. Wang, R. F. Frausto, and G. J. del Zoppo Fibronectin- and Vitronectin-Induced Microglial Activation and Matrix Metalloproteinase-9 Expression Is Mediated by Integrins {alpha}5beta1 and {alpha}vbeta5 J. Immunol., June 15, 2007; 178(12): 8158 - 8167. [Abstract] [Full Text] [PDF]

				J.-S. Park, M.-S. Woo, D.-H. Kim, J.-W. Hyun, W.-K. Kim, J.-C. Lee, and H.-S. Kim Anti-Inflammatory Mechanisms of Isoflavone Metabolites in Lipopolysaccharide-Stimulated Microglial Cells J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1237 - 1245. [Abstract] [Full Text] [PDF]

				Y. S. Kim, D. H. Choi, M. L. Block, S. Lorenzl, L. Yang, Y. J. Kim, S. Sugama, B. P. Cho, O. Hwang, S. E. Browne, et al. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation FASEB J, January 1, 2007; 21(1): 179 - 187. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help