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Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17077-82. Epub 2005 Nov 15.

Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages.

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1
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.

Abstract

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.

PMID:
16287979
PMCID:
PMC1287976
DOI:
10.1073/pnas.0504570102
[Indexed for MEDLINE]
Free PMC Article
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