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Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes.
The transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta are key regulators for the expression of the acute phase genes in the liver, such as complement component C3 and antichymotrypsin. In the brain, these acute phase proteins are produced in response to pro-inflammatory cytokines by the reactive astrocytes, in particular those surrounding the amyloid plaques of Alzheimer's disease brains. Here we show that lipopolysaccharides (LPS), IL-1beta, and TNFalpha induce the expression of the c/ebpbeta and -delta genes in mouse primary astrocytes. This induction precedes the expression of the acute phase genes coding for the complement component C3 and the mouse homologue of antichymotrypsin. The induction of these two acute phase genes by LPS is blocked by cycloheximide, whereas this protein synthesis inhibitor does not affect the expression of the c/ebp genes. Altogether, our data support a role as immediate-early genes for c/ebpbeta and -delta, whose expression is induced by pro-inflammatory cytokines in mouse cortical astrocytes. In the liver, these transcription factors are known to play an important role in inflammation and energy metabolism regulation. Therefore, C/EBPbeta and -delta could be pivotal transcription factors involved in brain inflammation, in addition to their previously demonstrated role in brain glycogen metabolism regulation (Cardinaux and Magistretti. J Neurosci 16:919-929, 1996).
Animals, Astrocytes/cytology, Astrocytes/drug effects, Blotting, Northern, CCAAT-Enhancer-Binding Proteins, Cells, Cultured, Cerebral Cortex/cytology, Complement C3/biosynthesis, Complement C3/genetics, Cycloheximide/pharmacology, Cytokines/metabolism, Cytokines/pharmacology, DNA-Binding Proteins/biosynthesis, DNA-Binding Proteins/genetics, Gene Expression/drug effects, Interferon-gamma/pharmacology, Interleukin-1/pharmacology, Interleukin-6/pharmacology, Lipopolysaccharides/pharmacology, Mice, Nuclear Proteins/biosynthesis, Nuclear Proteins/genetics, Protein Isoforms/biosynthesis, Protein Isoforms/genetics, Protein Synthesis Inhibitors/pharmacology, RNA, Messenger/biosynthesis, Serpins, Transcription Factors/biosynthesis, Transcription Factors/genetics, Trypsin Inhibitors/biosynthesis, Trypsin Inhibitors/genetics, Tumor Necrosis Factor-alpha/pharmacology
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