BACKGROUND/AIMS: The anti-inflammatory cytokine, interleukin-10 (IL-10), is known to exert a protective role in hepatic damage caused by viruses, alcohol, autoimmunity and a number of experimental aggressors. Recently, a protective role for IL-10 has also been proposed in diet-induced hepatic dysfunction. However, studies about the mechanisms involved in this process are controversial. The objective of this study was to evaluate the role of endogenous IL-10 in the development of hepatic insulin resistance, associated with diet-induced fatty liver disease. METHODS: Male Swiss mice treated for eight weeks with a high-fat diet became diabetic and developed non-alcoholic fatty liver disease, which is characterized by increased hepatic fat deposition and liver infiltration by F4/80 positive cells. This was accompanied by an increased hepatic expression of TNF-alpha, IL-6, IL-1beta and IL-10, and by an impaired insulin signal transduction through the insulin receptor/IRS1-IRS2/PI3-kinase/Akt/FOXO1 signaling pathway. RESULTS: Upon endogenous IL-10 inhibition for 5 days, using two distinct methods, a neutralizing anti-IL-10 antibody and an antisense oligonucleotide against IL-10, increased hepatic expression of the inflammatory markers TNF-alpha, IL-6, IL-1beta and F4/80 was observed. This was accompanied by a significant negative modulation of insulin signal transduction through insulin receptor/IRS1-IRS2/PI3-kinase/Akt/FOXO1, and by the stimulation of hepatic signaling proteins involved in gluconeogenesis and lipid synthesis. CONCLUSIONS: Thus, in an animal model of diet-induced fatty liver disease, the inhibition of IL-10 promotes the increased expression of inflammatory cytokines, the worsening of insulin signaling and the activation of gluconeogenic and lipidogenic pathways.
BACKGROUND/AIMS: The anti-inflammatory cytokine, interleukin-10 (IL-10), is known to exert a protective role in hepatic damage caused by viruses, alcohol, autoimmunity and a number of experimental aggressors. Recently, a protective role for IL-10 has also been proposed in diet-induced hepatic dysfunction. However, studies about the mechanisms involved in this process are controversial. The objective of this study was to evaluate the role of endogenous IL-10 in the development of hepatic insulin resistance, associated with diet-induced fatty liver disease. METHODS: Male Swiss mice treated for eight weeks with a high-fat diet became diabetic and developed non-alcoholic fatty liver disease, which is characterized by increased hepatic fat deposition and liver infiltration by F4/80 positive cells. This was accompanied by an increased hepatic expression of TNF-alpha, IL-6, IL-1beta and IL-10, and by an impaired insulin signal transduction through the insulin receptor/IRS1-IRS2/PI3-kinase/Akt/FOXO1 signaling pathway. RESULTS: Upon endogenous IL-10 inhibition for 5 days, using two distinct methods, a neutralizing anti-IL-10 antibody and an antisense oligonucleotide against IL-10, increased hepatic expression of the inflammatory markers TNF-alpha, IL-6, IL-1beta and F4/80 was observed. This was accompanied by a significant negative modulation of insulin signal transduction through insulin receptor/IRS1-IRS2/PI3-kinase/Akt/FOXO1, and by the stimulation of hepatic signaling proteins involved in gluconeogenesis and lipid synthesis. CONCLUSIONS: Thus, in an animal model of diet-induced fatty liver disease, the inhibition of IL-10 promotes the increased expression of inflammatory cytokines, the worsening of insulin signaling and the activation of gluconeogenic and lipidogenic pathways.
Authors: Daniel A Winer; Shawn Winer; Lei Shen; Persis P Wadia; Jason Yantha; Geoffrey Paltser; Hubert Tsui; Ping Wu; Matthew G Davidson; Michael N Alonso; Hwei X Leong; Alec Glassford; Maria Caimol; Justin A Kenkel; Thomas F Tedder; Tracey McLaughlin; David B Miklos; H-Michael Dosch; Edgar G Engleman Journal: Nat Med Date: 2011-04-17 Impact factor: 53.440
Authors: Vincent Braunersreuther; Giorgio Luciano Viviani; François Mach; Fabrizio Montecucco Journal: World J Gastroenterol Date: 2012-02-28 Impact factor: 5.742
Authors: Florian W Kiefer; Maximilian Zeyda; Karina Gollinger; Birgit Pfau; Angelika Neuhofer; Thomas Weichhart; Marcus D Säemann; René Geyeregger; Michaela Schlederer; Lukas Kenner; Thomas M Stulnig Journal: Diabetes Date: 2010-01-27 Impact factor: 9.461