Norepinephrine Stimulates Interleukin-6 mRNA Expression in Primary Cultured Rat Hepatocytes

Abstract

Non-invasive immobilization stress causes an increase in the plasma interleukin (IL)-6 level accompanied by increased IL-6 mRNA expression and IL-6 immunoactivity in the liver [Biochem. Biophys. Res. Commun. (1997) 238, 707-711]. In the present study, using rat primary cultured hepatocytes and non-parenchymal liver cells, the effect of norepinephrine (NE) on IL-6 mRNA expression was determined. IL-6 mRNA expression in hepatocytes, but not in non-parenchymal liver cells, increased when the cells were treated with NE. The stimulatory effect of NE was inhibited by the combined use of alpha- and beta-adrenergic antagonists. IL-6 mRNA expression in hepatocytes also increased on incubation with the culture medium of non-parenchymal liver cells treated with NE. The effect of the medium was blocked by an IL-1 receptor antagonist. Moreover, exogenous IL-1beta stimulated IL-6 mRNA expression in hepatocytes. IL-1beta was present in the medium of non-parenchymal liver cells and increased with NE-treatment. These results suggest that NE released from sympathetic nerve terminals during stress can directly increase IL-6 mRNA expression in hepatocytes and indirectly through IL-1beta production from non-parenchymal liver cells.

Genetic Profiling of α1-Adrenergic Receptor Subtypes by Oligonucleotide Microarrays: Coupling to Interleukin-6 Secretion but Differences in STAT3 Phosphorylation and gp-130

“…IL-6 is reported to increase in astrocytes and hepatocytes upon ␣ 1 -AR stimulation (Norris and Benveniste, 1993;Jung et al, 2000), confirming that our microarray data can be translated to endogenous systems. In addition, the ␣ 1B -AR transgenic mouse model also constitutively down-regulated gp-130 protein levels in the heart (Yun et al, 2003), again confirming the fibroblast results.…”

Sympathetic Activation of Hepatic and Splenic IL-1β mRNA Expression during Oscillation Stress in the Rat

“…In fact, very recently we demonstrated that norepinephrine enhances IL-6 mRNA expression in primary cultured rat hepatocytes [7]. Moreover, we found that norepinephrine increases IL-1β production in non-parenchymal liver cells [7]. This latter observation seems compatible to the previous report that the IL-1 secretion in cultured monocytes is increased by physiological concentrations of epinephrine [1].…”

“…The stress-induced IL-6 production has been suggested to be mediated through activation of sympathetic nerves more than adrenal secretions [17]. In fact, very recently we demonstrated that norepinephrine enhances IL-6 mRNA expression in primary cultured rat hepatocytes [7]. Moreover, we found that norepinephrine increases IL-1β production in non-parenchymal liver cells [7].…”

“…Physiological relevance of IL-1β expression in the liver and spleen during oscillation stress is at present unknown. We have recently demonstrated that norepinephrine increase IL-1 production in non-parenchymal liver cells, which in turn induces IL-6 mRNA expression in hepatocytes [7]. Moreover, it has been established that sympathetically mediated IL-6 production in the liver is enhanced by noninvasive stress such as immobilization [3,8,17,18].…”

Novel α1-Adrenergic Receptor Signaling Pathways: Secreted Factors and Interactions with the Extracellular Matrix

“…In addition to our previous study, which demonstrated ␣ 1 -AR subtypedependent effects on IL-6/gp130/stat3 signaling (GonzalezCabrera et al, 2003), the up-regulation of IL-6 mRNA and protein secretion was also reported in astrocytes and hepatocytes after ␣ 1 -AR activation (Norris and Benveniste, 1993;Jung et al, 2000). We also confirmed that IL-6 secretion was maintained by Western blot after 18 h of ␣ 1A -AR stimulation (Fig.…”