Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages.
This study demonstrates that pretreatment with polyinosinic-polycytidylic acid (poly I:C) significantly decreased the mortality and liver injury caused by injection of lipopolysaccharide (LPS) in the presence of d-galactosamine (d-GalN) in C57BL/6 mice. Depletion of natural killer, natural killer T, and T cells did not change the protective effect of poly I:C on LPS/d-GalN-induced liver injury in vivo. However, depletion of macrophages abolished LPS/d-GalN-induced fulminant hepatitis, which could be restored by adoptive transfer of macrophages but not by transfer of poly I:C-treated macrophages. Treatment with poly I:C down-regulated the expression of the toll-like receptor 4 (TLR4) on macrophages and reduced the sensitivity of macrophages (Kupffer cells and peritoneal macrophages from C57BL/6 mice, or RAW264.7 cells) to LPS stimulation. Poly I:C pretreatment also impaired the signaling of mitogen-activated protein kinases and NF-kappaB induced by LPS in RAW264.7 cells. Blockade of TLR3 with a TLR3 antibody abolished poly I:C down-regulation of TLR4 expression and LPS stimulation of TNF-alpha production in RAW264.7 cells. Taken together, our findings suggest that activation of TLR3 by its ligand, poly I:C, induced LPS tolerance by down-regulation of TLR4 expression on macrophages.
Jiang
Wei
W
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
Sun
Rui
R
Wei
Haiming
H
Tian
Zhigang
Z
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008024:Ligands; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000008:administration & dosage / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D008024:Ligands; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D011070:Poly I-C