Inhibition by recombinant human interleukin-6 of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase and of the insulin-dependent induction of glucokinase gene expression in cultured rat hepatocytes: Regulation of gene transcription and messenger RNA degradation

Abstract

The influence of recombinant human interleukin-6, the major mediator of the inflammatory response in liver, on the glucagon- and insulin-dependent induction of the phosphoenolpyruvate carboxykinase and glucokinase gene, respectively, was monitored on the level of gene transcription, mRNA abundance and enzyme activity in cultured rat hepatocytes. As control markers of the interleukin-6-induced acute-phase response the mRNA levels of the acute phase proteins alpha 2-macroglobulin and beta-fibrinogen were determined. In cultured rat hepatocytes, recombinant human interleukin-6, added simultaneously with glucagon and insulin, lowered the maximal increase in glucagon-induced phosphoenolpyruvate carboxykinase mRNA levels after 2 hr and the maximal increase in glucokinase mRNA levels after 3 hr to about 30%, respectively. It inhibited the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene transcription and phosphoenolpyruvate carboxykinase enzyme activity, as well as the insulin-induced increases in glucokinase gene transcription and glucokinase enzyme activity. Recombinant human interleukin-6 increased the mRNA levels of the acute-phase proteins alpha 2-macroglobulin and beta-fibrinogen gradually over 4 to 6 hr. Recombinant human interleukin-6, added 2 hr after glucagon or 3 hr after insulin at the maximum of the hormone-induced enzyme mRNA levels, almost doubled the decay rate of phosphoenolpyruvate carboxykinase mRNA and glucokinase mRNA. The results show that interleukin-6 induced the expression of inflammatory proteins and simultaneously inhibited the hormone-induced expression of enzymes of intermediary metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-6 and insulin sensitivity: friend or foe?

“…This may suggest that IL-6 can actually improve hepatic insulin resistance in patients with Type 2 diabetes. In contrast, IL-6 also inhibits insulin activation of glucokinase [85] while it has been shown to induce hepatic triglyceride secretion in rats [86]. As discussed, chronic treatment with IL-6 induces hepatic insulin resistance in rats, due to marked reductions in insulin receptor autophosphorylation and IRS-1 tyrosine phosphorylation [64].…”

Induction by interleukin 6 of Gs-coupled prostaglandin E2 receptors in rat hepatocytes mediating a prostaglandin E2-dependent inhibition of the hepatocyte’s acute phase response

“…PGE 2 has previously been shown to mimic the action of IL-6 as an inhibitor of the glucagon-elicited induction of the key gluconeogenetic enzyme phosphoenolpyruvate carboxykinase via the G i -linked EP3-R. 45 This inhibition of the glucagoninduced transcription of the phosphoenolpyruvate carboxykinase gene may represent the hepatocyte' s strategy to economize its resources for the acute phase response. 46 PGE 2 has also been shown to increase the ␣ 2 -MG formation in unstimulated hepatocytes 21 via an as yet unidentified receptor. These actions of PGE 2 indicate that it may be considered an enhancer of the acute phase reaction.…”

IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise

“…IL-6 has also been implicated in the regulation of these genes. Studies using cultured rat hepatocytes showed that incubation with IL-6 attenuated glucagon-induced Pepck (also known as Pck1) expression [4] or inhibited dexamethasone/cAMP-induced Pepck and G6pase (also known as G6pc) expression [5]. Intraperitoneal application of IL-6 inhibited the increase in Pepck mRNA during the initial phase of fasting in rats [6].…”