TY - JOUR
T1 - Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice
AU - Byun, Jin Seok
AU - Suh, Yang Gun
AU - Yi, Hyon Seung
AU - Lee, Young Sun
AU - Jeong, Won Il
N1 - Funding Information:
The Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea ( A111498 , A111345 ) and The Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Science and Technology ( 2011-0029328 ).
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Endocannabinoid
KW - Poly I:C
KW - Steatohepatitis
KW - Toll-like receptor 4
UR - http://www.scopus.com/inward/record.url?scp=84872366958&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2012.09.016
DO - 10.1016/j.jhep.2012.09.016
M3 - Article
C2 - 23023014
AN - SCOPUS:84872366958
VL - 58
SP - 342
EP - 349
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 2
ER -