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 polyinosinicpolycytidylic acid (poly I:C) significantly decreased the mortality and liver injury caused by injection of lipopolysaccharicle (LPS) in the presence Of D-galactosamine (D-GaIN) 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-GaIN-induced liver injury in vivo. However, depletion of macrophages abolished LPS/D-GaIN-induced fulminant hepatitis, which could be restored by adoptive transfer of macrophages but not by transfer of poly K-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 l:C pretreatment also impaired the signaling of mitogen-activated protein kinases and NF-kappa B 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.