Journal article
Kupffer cell cytokines interleukin-1β and interleukin-10 combine to inhibit phosphoenolpyruvate carboxykinase and gluconeogenesis in cultured hepatocytes
The International Journal of Biochemistry & Cell Biology, Vol.36(8), pp.1462-1472
2004
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.
Details
- Title
- Kupffer cell cytokines interleukin-1β and interleukin-10 combine to inhibit phosphoenolpyruvate carboxykinase and gluconeogenesis in cultured hepatocytes
- Authors/Creators
- S.T. Yerkovich (Author/Creator) - The University of Western AustraliaP.J. Rigby (Author/Creator) - The University of Western AustraliaP.A. Fournier (Author/Creator) - The University of Western AustraliaJ.K. Olynyk (Author/Creator) - School of Medicine and PharmacologyG.C.T. Yeoh (Author/Creator) - School of Molecular Sciences
- Publication Details
- The International Journal of Biochemistry & Cell Biology, Vol.36(8), pp.1462-1472
- Publisher
- Elsevier Limited
- Identifiers
- 991005541975707891
- Copyright
- © 2003 Elsevier Ltd.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Citation topics
- 1 Clinical & Life Sciences
- 1.6 Immunology
- 1.6.351 Sepsis Immunology
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- ESI research areas
- Biology & Biochemistry