Kupffer cell cytokines interleukin-1β and interleukin-10 combine to inhibit phosphoenolpyruvate carboxykinase and gluconeogenesis in cultured hepatocytes

Yerkovich, S. T., Rigby, P. J., Fournier, P. A., Olynyk, J. K. and Yeoh, G. C. T. (2004) Kupffer cell cytokines interleukin-1β and interleukin-10 combine to inhibit phosphoenolpyruvate carboxykinase and gluconeogenesis in cultured hepatocytes. International Journal of Biochemistry and Cell Biology, 36 8: 1462-1472. doi:10.1016/j.biocel.2003.10.022


Author Yerkovich, S. T.
Rigby, P. J.
Fournier, P. A.
Olynyk, J. K.
Yeoh, G. C. T.
Title Kupffer cell cytokines interleukin-1β and interleukin-10 combine to inhibit phosphoenolpyruvate carboxykinase and gluconeogenesis in cultured hepatocytes
Journal name International Journal of Biochemistry and Cell Biology   Check publisher's open access policy
ISSN 1357-2725
Publication date 2004-08-01
Sub-type Article (original research)
DOI 10.1016/j.biocel.2003.10.022
Open Access Status
Volume 36
Issue 8
Start page 1462
End page 1472
Total pages 11
Place of publication Exeter, England
Publisher Elsevier/Pergamon
Language eng
Subject 060104 Cell Metabolism
Abstract Background and aims: Recent evidence suggests that inflammatory cytokines may mediate reduced hepatic glucose production and reduced blood glucose concentrations in sepsis. Therefore the aim of this study is to provide direct evidence of a cytokine-mediated interaction between Kupffer cells and hepatocytes by characterising the effects of lipopolysaccharide-stimulated Kupffer cells on hepatocyte gluconeogenesis, and the activity of key regulatory enzymes of this pathway. Methods and results: Primary isolates of hepatocytes co-cultured with lipopolysaccharide-stimulated Kupffer cells in Transwell inserts showed a 48% inhibition of gluconeogenesis (P<0.001). RNase protection assay and ELISA of Kupffer cells and the culture media following exposure to lipopolysaccharide showed increased levels of interleukin-1 alpha and beta, tumour necrosis factor alpha and IL-10. The addition of IL-1β and IL-10 to hepatocyte cultures inhibited gluconeogenesis by 52% (P<0.001), whereas each cytokine alone was ineffective. To determine whether altered production or activity of phosphoenolpyruvate carboxykinase or pyruvate kinase was responsible for the reduced glucose synthesis, their mRNA, protein levels and enzyme activities were measured. Primary hepatocytes co-cultured with lipopolysaccharide-stimulated Kupffer cells or cultured with a combination of IL-1β and IL-10 displayed reduced levels of phosphoenolpyruvate carboxykinase mRNA, protein and enzyme activity. In contrast the mRNA, protein levels and enzyme activity of pyruvate kinase were not altered; suggesting that gluconeogenesis was suppressed by downregulation of phosphoenolpyruvate carboxykinase. Conclusions: Therefore, hypoglycaemia, which is often observed in sepsis, may be mediated by Kupffer cell-derived IL-1β and IL-10. In addition this study suggests these cytokines inhibit phosphoenolpyruvate carboxykinase production and thereby hepatic gluconeogenesis.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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