CD14 is not required for carbon tetrachloride‐induced hepatic inflammation and fibrosis with or without lipopolysaccharide challenge

Abstract

AbstractBinding of lipopolysaccharide (LPS) to CD14 is required for its cellular effects via TLR4. A role of LPS/TLR4‐mediated signaling in activated hepatic stellate cells (aHSCs), the major fibrogenic cells, in liver fibrosis has been reported. We investigated effects of LPS on carbon tetrachloride (CCl4)‐induced fibrosis in CD14‐knockout (KO) mice in vivo, and culture‐activated HSCs in vitro. CCl4 (biweekly; 4 weeks)‐treated wild type (WT) and CD14‐KO mice were challenged with single LPS administration for 24 h. Liver injury, inflammation and fibrosis were determined. Culture‐activated HSCs from WT or CD14‐KO mice were stimulated with LPS. Parameters of fibrogenic activity (expression of collagen1a1 [Col1a1], α‐smooth muscle actin [αSMA] and TGFβ1) and inflammatory cytokines/chemokines were measured. CCl4 treatment caused similar liver injury and fibrosis in WT and CD14‐KO mice. LPS increased liver injury and inflammation similarly in CCl4‐treated WT and CD14‐KO mice, but downregulated Timp1 and upregulated Mmp13. LPS elicited similar NFκB activation and inflammatory response in WT and CD14‐KO aHSCs. LPS similarly downregulated Acta2 (encodes αSMA), Pdgfrb, Col1a1 and Mmp13 expression but did not affect Timp1 expression in WT and CD14‐KO aHSCs. LPS did not alter Tgfb1 but increased expression of decorin (Dcn) (inhibitor of TGFβ1) expression in WT and CD14‐KO aHSCs. The results indicate that the effects of LPS on HSCs are CD14‐independent, and CD14 is not required for hepatic fibrosis. LPS‐induced down‐modulation of fibrogenic markers in aHSCs is also CD14‐independent.