Norepinephrine increases I kappa B alpha expression in astrocytes.
The neurotransmitter norepinephrine (NE) can inhibit inflammatory gene expression in glial cells; however, the mechanisms involved are not clear. In primary astrocytes, NE dose-dependently increased the expression of inhibitory I kappa B alpha protein accompanied by an increase in steady state levels of I kappa B alpha mRNA. Maximal increases were observed at 30-60 min for the mRNA and at 4 h for protein, and these effects were mediated by NE binding to beta-adrenergic receptors. NE activated a 1.3-kilobase I kappa B alpha promoter transfected into astrocytes or C6 glioma cells, and this activation was prevented by a beta-antagonist and by protein kinase A inhibitors but not by an NF kappa B inhibitor. NE increased I kappa B alpha protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of I kappa B alpha. I kappa B alpha was detected in the frontal cortex of normal adult rats, and its levels were reduced if central NE levels were depleted by lesion of the locus ceruleus. The reduction of brain I kappa B alpha levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that I kappa B alpha expression is regulated by NE at both transcriptional and post-transcriptional levels, which could contribute to the observed anti-inflammatory properties of NE in vitro and in vivo.
Gavrilyuk
Vitaliy
V
Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Dello Russo
Cinzia
C
Heneka
Michael T
MT
Pelligrino
Dale
D
Weinberg
Guy
G
Feinstein
Douglas L
DL
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D009638:Norepinephrine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine