Defective transcription factor activation for proinflammatory gene expression in poly(ADP-ribose) polymerase 1-deficient glia

被引:50
作者
Ha, HC [1 ]
机构
[1] Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20057 USA
关键词
D O I
10.1073/pnas.0306895101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Poly(ADP-ribose) polymerase 1 (PARP-1) activity is detected in both neuronal and nonneuronal cells in the CNS, and excessive PARP-1 activity is known to be detrimental to tissue because of the cellular energy loss. Accordingly, PARP-1-deficient (PARP-1(-/-)) mice have been shown to be resistant to cerebral ischemia and several forms of inflammation. Recently, PARP-1 in glial cells has been shown to mediate the expression of proinflammatory genes in response to inflammatory stimuli by, in part, enhancing cognate DNA-binding capacities of transcription factors such as NF-kappaB and activator protein 1. Here, we demonstrate an additional mechanism whereby a significant reduction of proinflammatory gene expression such as IL-1beta, tumor necrosis factor alpha, and inducible nitric-oxide synthase in PARP-1(-/-) glial cells is linked to defective inflammatory stimuli-induced p38(MAPK)-mediated phosphorylation of ATF-2 and cAMP-response element-binding protein and phosphorylation of NF-kappaB p65. Importantly, an inflammatory stimuli-induced p38(MAPK) activation is impaired in PARP(-/-) glial cells in a signaling pathway- and cell/tissue type-specific manner. These findings indicate that PARP-1 is an essential host factor among factors that actively mediate excessive production of proinflammatory molecules in glial cells, which may in turn contribute to the initiation of neuronal injuries.
引用
收藏
页码:5087 / 5092
页数:6
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