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

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National Academy of Sciences

RESUMO

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-κB and activator protein 1. Here, we demonstrate an additional mechanism whereby a significant reduction of proinflammatory gene expression such as IL-1β, tumor necrosis factor α, and inducible nitricoxide synthase in PARP-1-/- glial cells is linked to defective inflammatory stimuli-induced p38MAPK-mediated phosphorylation of ATF-2 and cAMP-response element-binding protein and phosphorylation of NF-κB p65. Importantly, an inflammatory stimuli-induced p38MAPK activation is impaired in PARP-1-/- 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.

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