Recent evidence indicates that inflammatory cytokines are involved in changes of blood glucose concentrations and hepatic glucose metabolism in infectious diseases, including sepsis. However, little is known regarding how cytokines interact with glucoregulatory hormones such as insulin. The objective of the present study is to investigate if and how cytokines influence insulin-stimulated glycogen metabolism in the liver. Interleukin 1␤ (IL-1␤) and interleukin 6 (IL-6) markedly inhibited the increase of glycogen deposition stimulated by insulin in primary rat hepatocyte cultures; however, tumor necrosis factor ␣ had no effect. Labeling experiments revealed that both cytokines counteracted insulin action by decreasing The regulation of carbohydrate metabolism, including glucose input and output, is one of the liver' s most important functions in the homeostasis of glucose concentration. Classical hormones such as insulin, glucagon, glucocorticoid, and adrenaline, contribute largely to the maintenance of glucose concentration as well as to general physiological homeostasis. During septic shock associated with severe infectious diseases, there are marked changes in blood glucose and its metabolism in various organs including liver, adipose tissue and skeletal muscle. 1 These alterations come mainly from imbalanced, and usually increased, concentrations of glucoregulatory and stress hormones. 2,3 However, such a change in the hormone concentrations does not explain every alteration occurring in the blood and tissues, 4 implying that additional factors contribute to the changes of glucose metabolism.Recently, considerable attention has been given to the effects of inflammatory cytokines in the liver. 5 These cytokines are produced by lymphocytes, macrophages, or other cells as part of the inflammatory reactions to trauma, infection, and malignancy; these cells also mediate the interaction among different cells and tissues. The administration of interleukin 1 (IL-1), tumor necrosis factor ␣ (TNF␣), or a combination of both results in hyperglycemia followed by hypoglycemia in animals. 4,[6][7][8] The administration of TNF␣ to rats impairs insulin action on peripheral glucose consumption and hepatic glucose output, 9 suggesting that cytokines are involved in the decreased tissue sensitivity to insulin. 10,11 Furthermore, it is reported that IL-1␤ stimulated glycogen degradation concomitantly with the decrease of glycogen synthase activity 12 and that IL-1␣ and IL-6 inhibited glycogen synthesis and stimulated glycogen degradation 13 in isolated rat hepatocytes. Ritchie 14 demonstrated that IL-6, but not IL-1, stimulated [ 14 C]-glucose release from [ 14 C]-glycogenlabeled hepatocytes.Accumulating evidence indicates that cytokines are potential mediators of abnormalities in glucose homeostasis, interacting with above glucoregulatory hormones and modifying their actions. However, it is obscure which cytokines interact with glucoregulatory hormones in hepatic glucose metabolism. In the present study, we investigate the effec...

responses. 1 In vivo, NO has been reported to have pro-LPS stimulated NO formation in a dose-dependent manner and induced half-maximal effects at 30 pmol/L. Maxi-tective effects during the inflammation and endotoxemal stimulation was achieved at 12 to 16 hours after the mia associated with hepatic injury. 2 In contrast, NO addition of 1 nmol/L of IL-1b, and was 50-to 60-fold above has also been reported to induce hepatic mitochondrial basal levels in rat hepatocytes. The combined effect of dysfunction both in perfused liver and isolated hepatothese cytokines with LPS or IFN-g on NO formation was cytes. 3 Interleukin (IL)1b, tumor necrosis factor a also examined. Neither LPS nor IFN-g affected the IL-(TNF-a), and endotoxins have all been shown to stimu1b-induced NO formation. TNF-a, however, stimulated late NO formation in hepatocytes and in Kupffer cells IL-1b-induced NO formation, while IL-6 inhibited it, al-cultured from chronically endotoxemic rats 4 or turpenthough independently these cytokines had no effect on tine-injected rats. 5 NO is synthesized from L-arginine NO formation. None of the cytokines tested stimulated by NO synthases (NOS). These enzymes can be classi-NO formation in cultured rat Kupffer cells. In hepatocytes, the NO formation induced by IL-1b was blocked by fied into at least two distinct groups. Constitutive NOS both the NO synthase (NOS) inhibitor N G -monomethyl-L-is present in endothelium 6 and in brain. 7 Inducible arginine (L-NMMA) and by IL-1 receptor antagonist (IL-NOS (iNOS) is present in negligible quantities under 1ra). Furthermore, IL-1b markedly increased NOS activ-physiological conditions, but is highly expressed in reity, and this increase in activity was accompanied by sponse to stimuli such as endotoxins and cytokines, the expression of inducible NOS (iNOS) messenger RNA in a variety of cells including vascular smooth muscle (mRNA). This study clearly demonstrated that IL-1b cells, 8,9 macrophages, 10 and liver cells. [11][12][13] Within the markedly stimulates NO formation in hepatocytes, in the liver, however, it is not clear whether the Kupffer cells or the hepatocytes are the primary producers of NO. In order to elucidate the mechanism by which cytokines induce NO formation within the liver, a sensitive Abbreviations: IL, interleukin; TNF-a, tumor necrosis factor a; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; chemiluminescence system was employed for the mea-

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Background: Nitric oxide (NO) has diverse activities under physiological and pathophysiological conditions in many types of cells. In cultured hepatocytes, NO is produced by inducible NO synthase (iNOS) in response to interleukin (IL)-1␤. Cis-controlling elements and transcription factors which were involved in iNOS gene expression in hepatocytes have been unclear.

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