title: CCAAT/enhancer binding protein δ regulates glial proinflammatory gene expression.
abstract: The transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) is expressed in activated astrocytes and microglia and can regulate the expression of potentially detrimental proinflammatory genes. The objective of this study was to determine the role of C/EBPδ in glial activation. To this end, glial activation was analyzed in primary glial cultures and in the central nervous system from wild type and C/EBPδ(-/-) mice. In vitro studies showed that the expression of proinflammatory genes nitric oxide (NO)synthase-2, cyclooxygenase-2, and interleukin (IL)-6 in glial cultures, and the neurotoxicity elicited by microglia in neuron-microglia cocultures, were decreased in the absence of C/EBPδ when cultures were treated with lipopolysaccharide (LPS) and interferon γ, but not with LPS alone. In C/EBPδ(-/-) mice, systemic LPS-induced brain expression of NO synthase-2, tumor necrosis factor-α, IL-1β, and IL-6 was attenuated. Finally, increased C/EBPδ nuclear expression was observed in microglial cells from amyotrophic lateral sclerosis patients and G93A-SOD1 mice spinal cord. These results demonstrate that C/EBPδ plays a key role in the regulation of proinflammatory gene expression in glial activation and suggest that C/EBPδ inhibition has potential for the treatment of neurodegenerative disorders, in particular, amyotrophic lateral sclerosis.
authors.affiliation: Biochemistry and Molecular Biology Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: Tony
authors.initials: T
authors.lastname: Valente
authors.forename: Marco
authors.initials: M
authors.lastname: Straccia
authors.forename: Nuria
authors.initials: N
authors.lastname: Gresa-Arribas
authors.forename: Guido
authors.initials: G
authors.lastname: Dentesano
authors.forename: Josep M
authors.initials: JM
authors.lastname: Tusell
authors.forename: Joan
authors.initials: J
authors.lastname: Serratosa
authors.forename: Pilar
authors.initials: P
authors.lastname: Mancera
authors.forename: Carme
authors.initials: C
authors.lastname: Solà
authors.forename: Josep
authors.initials: J
authors.lastname: Saura
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000628:therapy; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology* / Q000633:toxicity; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D058990:Molecular Targeted Therapy; D020078:Neurogenic Inflammation / Q000235:genetics* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D015850:Interleukin-6; C000606290:SOD1 protein, human; D051743:CCAAT-Enhancer-Binding Protein-delta; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1