Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death

被引:161
作者
Kauppinen, UM
Swanson, RA
机构
[1] Vet Affairs Med Ctr, San Francisco, CA 94121 USA
[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA
关键词
D O I
10.4049/jimmunol.174.4.2288
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Activated microglia contribute to cell death in ischemic and neurodegenerative disorders of the CNS. Microglial activation is regulated in part by NF-kappaB, and the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) enhances NF-kappaB binding to DNA. In this study, the role of PARP-1 in microglia-mediated neurotoxicity was assessed using microglia from wild-type (wt) and PARP-1(-/-) mice. Cultured microglia were incubated with TNF-alpha, a cytokine that is up-regulated in many neurological disorders. When stimulated with TNF-alpha, wt microglia proliferated, underwent morphological changes characteristic of activation, and killed neurons placed in coculture. The effects of TNF-alpha were markedly attenuated both in PARP-1(-/-) microglia and in wt microglia treated with the PARP enzymatic inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone. These effects were also blocked by (E)-3-(4-methylphenyisulfonyl)-2-propenenenitrile, which inhibits translocation of NF-kappaB to the nucleus. TNF-a also up-regulated microglial release of matrix metalloproteinase-9 (MMP-9), an enzyme with potential neurotoxic properties that is transcriptionally regulated by NF-kappaB. This up-regulation was blocked in PARP-1(-/-) microglia and in wt microglia by the PARP inhibitor 3,4-dihydro-5-[4-(I-piperidinyl)butoxy]-1(2h)-isoquinolinone. Microglia from MMP-9(-/-) mice were used to evaluate the contribution of MMP-9 to microglial neurotoxicity. MMP-9(-/-) microglia treated with TNF-alpha showed substantially reduced neurotoxicity relative to the wt microglia. TNF-alpha-stimulated wt microglia treated with the MMP inhibitor ilomastat also showed reduced neurotoxicity. These findings suggest that PARP-1 activation is required for both TNF-alpha-induced microglial activation and the neurotoxicity resulting from TNF-alpha-induced MMP-9 release.
引用
收藏
页码:2288 / 2296
页数:9
相关论文
共 68 条
[1]   Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes [J].
Avolio, C ;
Ruggieri, M ;
Giuliani, F ;
Liuzzi, GM ;
Leante, R ;
Riccio, P ;
Livrea, P ;
Trojano, M .
JOURNAL OF NEUROIMMUNOLOGY, 2003, 136 (1-2) :46-53
[2]   Inflammatory mediators and stroke: New opportunities for novel therapeutics [J].
Barone, FC ;
Feuerstein, GZ .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1999, 19 (08) :819-834
[3]   CXCR4-activated astrocyte glutamate release via TNFa: amplification by microglia triggers neurotoxicity [J].
Bezzi, P ;
Domercq, M ;
Brambilla, L ;
Galli, R ;
Schols, D ;
De Clercq, E ;
Vescovi, A ;
Bagetta, G ;
Kollias, G ;
Meldolesi, J ;
Volterra, A .
NATURE NEUROSCIENCE, 2001, 4 (07) :702-710
[4]   MODULATION OF POLY(ADP-RIBOSE) POLYMERASE DURING NEUTROPHILIC AND MONOCYTIC DIFFERENTIATION OF PROMYELOCYTIC (NB4) AND MYELOCYTIC (HL-60) LEUKEMIA-CELLS [J].
BHATIA, M ;
KIRKLAND, JB ;
MECKLINGGILL, KA .
BIOCHEMICAL JOURNAL, 1995, 308 :131-137
[5]  
Bitsch A, 2000, GLIA, V29, P366, DOI 10.1002/(SICI)1098-1136(20000215)29:4<366::AID-GLIA7>3.0.CO
[6]  
2-Y
[7]   Tissue inhibitors of metalloproteinases: evolution, structure and function [J].
Brew, K ;
Dinakarpandian, D ;
Nagase, H .
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY, 2000, 1477 (1-2) :267-283
[8]  
BURZIO LO, 1979, J BIOL CHEM, V254, P3029
[9]   THE AP-1 SITE IS REQUIRED FOR BASAL EXPRESSION BUT IS NOT NECESSARY FOR TPA-RESPONSE OF THE HUMAN STROMELYSIN GENE [J].
BUTTICE, G ;
QUINONES, S ;
KURKINEN, M .
NUCLEIC ACIDS RESEARCH, 1991, 19 (13) :3723-3731
[10]   The sequence-specific DNA binding of NF-κB is reversibly regulated by the automodification reaction of poly (ADP-ribose) polymerase 1 [J].
Chang, WJ ;
Alvarez-Gonzalez, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (50) :47664-47670