No abstract

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...

Antisense transcription is a widespread phenomenon in the mammalian genome and is believed to play a role in regulating gene expression. However, the exact functional significance of antisense transcription is largely unknown. Here, we show that natural antisense (AS) RNA is an important modulator of interferon-α1 (IFN-α1) mRNA levels. A ~4-kb, spliced IFN-α1 AS RNA targets a single-stranded region within a conserved secondary structure element of the IFN-α1 mRNA, an element which was previously reported to function as the nuclear export element. Following infection of human Namalwa lymphocytes with Sendai virus or infection of guinea pig 104C1 fetal fibroblasts with influenza virus A/PR/8/34, expression of IFN-α1 AS RNA becomes elevated. This elevated expression results in increased IFN-α1 mRNA stability because of the cytoplasmic (but not nuclear) interaction of the AS RNA with the mRNA at the single-stranded region. This results in increased IFN-α protein production. The silencing of IFN-α1 AS RNA by sense oligonucleotides or over-expression of antisense oligoribonucleotides, which were both designed from the target region, confirmed the critical role of the AS RNA in the post-transcriptional regulation of IFN-α1 mRNA levels. This AS RNA stabilization effect is caused by the prevention of the microRNA (miRNA)-induced destabilization of IFN-α1 mRNA due to masking of the miR-1270 binding site. This discovery not only reveals a regulatory pathway for controlling IFN-α1 gene expression during the host innate immune response against virus infection but also suggests a reason for the large number of overlapping complementary transcripts with previously unknown function.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-1216-x) contains supplementary material, which is available to authorized users.

No abstract