Norepinephrine increases IκBα 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 IkappaBalpha protein accompanied by an increase in steady state levels of IkappaBalpha 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 IkappaBalpha 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 NFkappaB inhibitor. NE increased IkappaBalpha protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of IkappaBalpha. IkappaBalpha 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 IkappaBalpha levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that IkappaBalpha 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.