Defective transcription factor activation for proinflammatory gene expression in poly(ADP-ribose) polymerase 1-deficient glia.
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 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-kappaB 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.
Ha
Hyo Chol
HC
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20057, USA. mcj22@georgetown.edu
D000818:Animals; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D018836:Inflammation Mediators; D014157:Transcription Factors; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases