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Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice

 Jin-Seok Byun  ;  Yang-Gun Suh  ;  Hyon-Seung Yi  ;  Young-Sun Lee  ;  Won-Il Jeong 
 JOURNAL OF HEPATOLOGY, Vol.58(2) : 342-349, 2013 
Journal Title
Issue Date
Animals ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Chemical and Drug Induced Liver Injury/prevention & control* ; Disease Models, Animal ; Ethanol/adverse effects* ; Fatty Liver/metabolism ; Fatty Liver/pathology ; Fatty Liver/prevention & control ; Hepatic Stellate Cells/drug effects ; Hepatic Stellate Cells/metabolism* ; Hepatic Stellate Cells/pathology ; In Vitro Techniques ; Interleukin-10/genetics ; Interleukin-10/metabolism* ; Kupffer Cells/drug effects ; Kupffer Cells/metabolism* ; Kupffer Cells/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Poly I-C/pharmacology ; Poly I-C/therapeutic use ; Signal Transduction/drug effects ; Toll-Like Receptor 3/drug effects ; Toll-Like Receptor 3/genetics ; Toll-Like Receptor 3/metabolism*
Toll-like receptor 4 ; Poly I:C ; Endocannabinoid ; Steatohepatitis
BACKGROUND & AIMS: The important function of toll-like receptor (TLR) 4 in Kupffer cells and hepatic stellate cells (HSCs) has been well documented in alcoholic liver injury. However, little is known about the role of TLR3. Thus, we tested whether TLR3 activation in HSCs and Kupffer cells could attenuate alcoholic liver injury in vivo, and investigated its possible mechanism in vitro. METHODS: Alcoholic liver injury was achieved by feeding wild type (WT), TLR3 knockout (TLR3(-/-)) and interleukin (IL)-10(-/-) mice with high-fat diet plus binge ethanol drinking for 2 weeks. To activate TLR3, polyinosinic-polycytidylic acid (poly I:C) was injected into mice. For in vitro studies, HSCs and Kupffer cells were isolated and treated with poly I:C. RESULTS: In WT mice, poly I:C treatment reduced alcoholic liver injury and fat accumulation by suppressing nuclear factor-κB activation and sterol response element-binding protein 1c expression in the liver. In addition, freshly isolated HSCs and Kupffer cells from poly I:C-treated mice showed enhanced expression of IL-10 compared to controls. Infiltrated macrophage numbers and the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1 and IL-6 on these cells were decreased after poly I:C treatment. In vitro, poly I:C treatment enhanced the expression of IL-10 via a TLR3-dependent mechanism in HSCs and Kupffer cells. Finally, the protective effects of poly I:C on alcoholic liver injury were diminished in TLR3(-/-) and IL-10(-/-) mice. CONCLUSIONS: TLR3 activation ameliorates alcoholic liver injury via the stimulation of IL-10 production in HSCs and Kupffer cells. TLR3 could be a novel therapeutic target for the treatment of alcoholic liver injury.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Suh, Yang Gun(서양권)
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