Glucagon-stimulated but not Isoproterenol-stimulated Glucose Formation Inhibition by Interleukin-6 in Primary Cultured Rat Hepatocytes

Abstract

During prolonged sepsis, impairment of glucose supply by the liver leads to hypoglycemia. Our aim was to investigate whether proinflammatory cytokine interleukin-6, a major mediator of the hepatic acute phase reaction, could contribute to this impairment by inhibiting hepatic glucose production stimulated by glucagon or isoproterenol in rat hepatocytes. Interleukin-6 inhibited the stimulation of glucose formation from glycogen by glucagon but not by isoproterenol in cultured rat hepatocytes. This was confirmed in the perfused rat liver. In cultured hepatocytes, the increase in cyclic adenosine-3',5'-monophosphate formation by glucagon was inhibited by interleukin-6, which was probably due to attenuation of glucagon binding to the glucagon receptor. The increase in cyclic adenosine-3',5'-monophosphate stimulated by isoproterenol was not affected by interleukin-6. However, the cytokine inhibited both expression of the key gluconeogenic control enzyme, phosphoenolpyruvate carboxykinase, stimulated by glucagon and isoproterenol. Thus, while increased glucose demand during the acute-phase reaction might initially be accomplished by catecholamine-mediated stimulation of glucose formation from glycogen, inhibition of gluconeogenesis by interleukin-6 may contribute to the impairment of glucose homeostasis during the prolonged acute phase reaction.

Key words

Phosphoenolpyruvate carboxykinase - glucagon receptor - glycogenolysis - isoproterenol - perfused rat liver - interleukin-6

References

• 1 Memon R A, Feingold K R, Grunfeld C. The effects of cytokines on intermediary metabolism.  The Endocrinologist . 1994;  4 56-63
• 2 Mizock B A. Alterations in carbohydrate metabolism during stress: a review of the literature.  Am J Med. 1995;  98 75-84
• 3 Christ B, Nath A. Impairment by IL1b and TNFa of the glucagon-induced phosphoenolpyruvate carboxykinase gene expression and gluconeogenesis in cultured rat hepatocytes.  Biochem J. 1996;  320 161-166
• 4 Christ B, Nath A, Heinrich P C, Jungermann K. 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.  Hepatology. 1994;  20 1577-1583
• 5 Berry L J, Smythe D S, Colwell L S. Inhibition of hepatic enzyme induction as a sensitive assay for endotoxin.  J Bacteriol. 1968;  96 1191-1199
• 6 Rippe D F, Berry L J. Study of inhibition of induction of phosphoenolpyruvate carboxykinase by endotoxin with radial immunodiffusion.  Infect Immunity. 1972;  6 766-772
• 7 Hill M, McCallum R. Altered transcriptional regulation of phosphoenolpyruvate carboxykinase in rats following endotoxin treatment.  J Clin Invest. 1991;  88 811-816
• 8 Hill M R, McCallum R E. Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice.  Infect Immunity. 1992;  60 4040-4050
• 9 Deutschman C S, DeMaio A, Clemens M G. Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene.  Am J Physiol. 1995;  269 R584-R591
• 10 Christ B, Nath A, Jungermann K. Mechanism of the impairment of the glucagon-stimulated phosphoenolpyruvate carboxykinase gene expression by IL6: Inhibition of the increase in cAMP and the downstream cAMP action.  Hepatology. 1997;  26 73-80
• 11 Christ B, Yazici E, Nath A. Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes.  Hepatology. 2000;  31 461-468
• 12 Bartels H, Linnemann H, Jungermann K. Predominant localization of phosphoenolpyruvate carboxykinase mRNA in the periportal zone of rat liver parenchyma demonstrated by in situ hybridization.  FEBS Lett. 1989;  248 188-194
• 13 Püschel G, Christ B. Inhibition by PGE2 of glucagon-induced increase in phosphoenolpyruvate carboxykinase mRNA and acceleration of mRNA degradation in cultured rat hepatocytes.  FEBS Lett. 1994;  351 353-356
• 14 Christ B, Probst I, Jungermann K. Antagonistic regulation of the glucose/glucose-6-phosphate cycle by insulin and glucagon in cultured hepatocytes.  Biochem J. 1986;  238 185-191
• 15 Jungermann K, Heilbronn R, Katz N, Sasse D. The glucose/glucose-6-phosphate cycle in the periportal and perivenous zone of rat liver.  Eur J Biochem. 1982;  123 429-436
• 16 Christ B, Jungermann K. Sub-compartmentation of the ‘cytosolic’ glucose 6-phosphate pool in cultured rat hepatocytes.  FEBS Lett. 1987;  221 375-380
• 17 Filkins J P. Monokines and the metabolic pathophysiology of septic shock.  Fed Proc. 1985;  44 300-304
• 18 Goto M, Zeller P, Lichtenberg R C. Decreased gluconeogenesis and increased glucose disposal without hyperinsulinemia in 10-day-old rats with endotoxic shock.  Metabolism. 1994;  43 1248-1254
• 19 Metzger S, Nusair S, Planer D, Barash V, Pappo O, Shilyansky J, Chajek-Shaul T. Inhibition of Hepatic Gluconeogenesis and Enhanced Glucose Uptake Contribute to the Development of Hypoglycemia in Mice Bearing Interleukin-1{beta}-Secreting Tumor.  Endocrinology. 2004;  145 5150-5156
• 20 Deutschman C S, DeMaio A, Buchman T G, Clemens M G. Sepsis-induced alterations in phosphoenolpyruvate carboxykinase expression: the role of insulin and glucagon.  Circ Shock. 1993;  40 295-302
• 21 Ceppi E D, Smith F S, Titheradge M A. Effect of multiple cytokines plus bacterial endotoxin on glucose and nitric oxide production by cultured rat hepatocytes.  Biochem J. 1996;  317 503-507
• 22 Tsigos C, Papanicolaou D A, Kyrou I, Defensor R, Mitsiadis C S, Chrousos G P. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation.  J Clin Endocrinol Metab. 1997;  82 4167-4170
• 23 Stouthard J M, Romijn J A, Van der Poll T, Endert E, Klein S, Bakker P J, Veenhof C H, Sauerwein H P. Endocrinologic and metabolic effects of interleukin-6 in humans.  Am J Physiol. 1995;  268 E813-E819
• 24 Lang C H, Bagby G J, Blakesley H L, Spitzer J J. Importance of hyperglucagonemia in eliciting the sepsis-induced increase in glucose production.  Circ Shock. 1989;  29 181-191
• 25 Byerley L O, Alcock N W, Starnes H FJ. Sepsis-induced cascade of cytokine mRNA expression: correlation with metabolic changes.  Am J Physiol. 1992;  261 E728-E735
• 26 DeBlasi A. Beta-adrenergic receptors: structure, function and regulation.  Drugs Exp Clin Res. 1990;  16 107-112
• 27 Burcelin R, Katz E B, Charron M J. Molecular and cellular aspects of the glucagon receptor: role in diabetes and metabolism.  Diabet and Metab. 1996;  22 373-396
• 28 Lai C F, Ripperger J, Wang Y, Kim H, Hawley R B, Baumann H. The STAT3-independent signaling pathway by glycoprotein 130 in hepatic cells.  J Biol Chem. 1999;  274 7793-7802
• 29 Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, Hashimoto N, Kido Y, Mori T, Sakaue H, Teshigawara K, Jin S, Iguchi H, Hiramatsu R, LeRoith D, Takeda K, Akira S, Kasuga M. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo.  Nat Med. 2004;  10 168-174
• 30 Sengupta T K, Schmitt E M, Ivashkiv L B. Inhibition of cytokines and JAK/STAT activation by distinct signaling pathways.  Proc Natl Acad Sci US. 1996;  93 9499-9504
• 31 Kojima H, Nakajima K, Hirano T. IL6-inducible complexes on an IL6 response element of the junB promotor contain STAT3 and 36 kDa CRE-like site binding protein(s).  Oncogene. 1996;  12 547-554
• 32 Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T. Transcriptional regulation of human prostaglandin-endoperoxidase synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells.  J Biol Chem. 1995;  270 24 965-24 971