Matrix metalloproteinase-3: A novel signaling proteinase from apoptotic neuronal cells that activates microglia
Matrix metalloproteinase-3: A novel signaling proteinase from apoptotic neuronal cells that activates microglia
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DOI：
10.1523/jneurosci.4346-04.2005
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发表时间：
2005-04-06
影响因子：
5.3
通讯作者：
Joh, TH
中科院分区：
文献类型：
--
作者：
Kim, YS;Kim, SS;Joh, TH
在神经退行性人类脑部疾病中，小胶质细胞的激活和炎症与进行性神经元凋亡有关。我们试图研究在凋亡性神经元变性中控制小胶质细胞激活的分子信号机制。本文报道PC12细胞在处理2-6h后，基质金属蛋白酶-3(MMP3)的活性形式被释放到PC12细胞的去血清培养液(SDM)和其他凋亡神经细胞的培养液中，SDM和重组MMP3的催化结构域(CMMP3)在原代培养的小胶质细胞以及小鼠小胶质细胞系BV2细胞中被激活。SDM和cMMP3均可诱导小胶质细胞产生肿瘤坏死因子α、白介素6、白介素1β和白介素1受体拮抗剂，但不能诱导内毒素容易诱导的白介素12和诱导型一氧化氮合酶的产生，提示小胶质细胞因子的诱导存在典型的神经元凋亡模式。既没有诱导胶质细胞源性神经营养因子，也没有诱导IL-10和转化生长因子-β1等抗炎细胞因子。SDM和cMMP3广泛地从小胶质细胞释放肿瘤坏死因子-α，并激活核因子-KB途径，而这些反应可被MMP3抑制剂NNGH[N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic酸预先孵育而完全取消]。MMP3介导的小胶质细胞激活主要依赖于ERK(细胞外信号调节激酶)的磷酸化，而不太依赖于JNK(c-jun氨基末端蛋白激酶)或p38的激活。SDM或cMMP3激活的BV2细胞条件培养液可诱导PC12细胞凋亡。这些结果强烈表明，神经元凋亡的独特信号是活性形式的基质金属蛋白酶-3的释放，激活小胶质细胞，继而加剧神经元的变性。因此，凋亡神经元释放的基质金属蛋白酶-3可能在帕金森氏症等退行性人类脑部疾病中起主要作用。
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 alpha(TNF alpha), interleukin-6 (IL-6), IL-1 beta, 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-beta 1, were induced. SDM and cMMP-3 extensively released TNF-alpha from microglia and activated the nuclear factor-KB 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.