Toll-Like Receptor 4–Independent Carbon Tetrachloride–Induced Fibrosis and Lipopolysaccharide-Induced Acute Liver Injury in Mice: Role of Hepatic Stellate Cells

Abstract

Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is implicated in acute and chronic liver injury; its effects are mediated predominantly via the membrane receptor Toll-like receptor 4 (TLR4). However, TLR4-independent effects of LPS may play important role in hepatic pathophysiology. We investigated carbon tetrachloride (CCl4)-induced fibrosis and LPS-induced acute liver injury in wild-type (WT) and B6.B10ScN-Tlr4lps-del/JthJ [TLR4-knockout (KO)] mice. Effects of LPS on fibrogenic hepatic stellate cells (HSCs) from WT and TLR4-KO mice were assessed invitro. CCl4 produced similar fibrosis and necroinflammation and increased the mRNA and protein expression of cytokines and chemokines in WT and TLR4-KO mice. However, circulating LPS concentration did not increase in CCl4-treated mice. Interestingly, LPS down-modulated α-smooth muscle actin (activated HSC marker) and collagen 1 in both WT and TLR4-KO HSCs. LPS induced similar activation of NF-κB, and stimulated the expression of cytokines and chemokines in WT and TLR4-KO HSCs. Finally, LPS caused similar inflammation and injury in previously untreated WT and TLR4-KO mice. The results provide evidence of the TLR4/LPS-independent mechanisms of liver fibrosis and also indicate that TLR4 is not entirely critical to LPS-induced acute liver injury. The results further indicate that LPS signaling in activated HSCs might be a mechanism of limiting liver fibrosis.