Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death.
نویسندگان
چکیده
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-methylphenylsulfonyl)-2-propenenenitrile, which inhibits translocation of NF-kappaB to the nucleus. TNF-alpha 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-(1-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.
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عنوان ژورنال:
- Journal of immunology
دوره 174 4 شماره
صفحات -
تاریخ انتشار 2005