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Background  Hepatic stellate cell (HSC) activation plays a pivotal role in hepatic inflammation and liver fibrosis. TLR4 pathway activation has been reported to be involved in mice liver fibrosis induced by hepatitis virus infection, alcohol abuse, biliary ligation, carbon tetrachloride 4 treatment, and  Schistosoma japonicum  ( Sj ) infection. The effect and mechanisms of the cyclooxygenase 2 (COX2)/prostanoid E2 (PGE2) axis on liver fibrosis induced by  Sj  are still unclear.    Methods  Mice liver fibrosis were induced by cutaneous infection of  Sj  cercariae. COX-2 inhibitor, NS398 were injected from week 5 to week 7, while TLR4 inhibitor TAK242 were injected from week 4 to week 8 post  Sj  infection. Human HSCs line, LX-2 cells were cultured and exposed to LPS or synthetic PGE2, or pretreated by TAK242, TLR4-siRNA or NS398. Liver tissue and serum or in vitro cultured cell lysaste were collected at indicated time courses for exploring the relationship between TLR4 and COX2-PGE2 axis through qPCR, western blot, immunohistochemical assay, ect. One-way analysis of variance among multiple groups followed by Uncorrected Fisher’s LSD- t  test or paired comparisons through  t  test were performed to tell the statistical differences.    Results  This study investigated the link between the COX2/PGE2 axis and TLR4 signaling in the induction of liver fibrogenesis in mice during  Sj  infection and in vitro culture of HSC strain-LX-2. The COX2/PGE2 axis was positively associated with  Sj -induced liver fibrosis. TLR4 pathway activation stimulated the COX2/PGE2 axis in  Sj- infected mice and in lipopolysaccharide (LPS)-exposed cultured HSCs. Synthetic PGE2 activated cultured HSCs through upregulation of alpha smooth muscle actin (α-SMA) expression. In LPS-triggered HSCs, NS398, a COX2 inhibitor, led to suppression of PGE2 synthesis and reduced expression of α-SMA and type I collagen (COL I).    Conclusions  These results indicate firstly the positive association of the COX2/PGE2 axis with liver fibrosis induced by  Sj  infection. TLR4 signaling may at least partially control the COX2/PGE2 axis in  Sj -infected mice liver and in vitro cultured HSCs. The COX2/PGE2-EP2/EP4 axis might be a good drug target against liver fibrosis induced by  Sj  infection.    Graphic abstract

Involvement of TLR4 signaling regulated-COX2/PGE2 axis in liver fibrosis induced by Schistosoma japonicum infection