title: Inhibition of MAPK and NF-κB signaling pathways alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in Toll-like receptor 5 (TLR5) deficiency mice.
abstract: Current researches showed that TLR family plays an important role in liver fibrosis, yet the molecular mechanism by which this occurs is not fully explained. In this study, we investigated the role of TLR5 in carbon tetrachloride-induced liver fibrosis, and further examined wether TLR5 knockout attenuated tetrachloride-induced liver fibrosis by inhibiting hepatic stellate cells activation via modulating NF-κB and MAPK signaling pathways. Our results found that carbon tetrachloride induced liver function injury in WT mice with a inflammatory responses through the activation of NF-κB and MAPK signaling pathways, resulting in hepatic stellate cells activation. In contrast, TLR5 deficiency mice after carbon tetrachloride administration reduced NF-κB and MAPK signaling pathways activation, which down regulated hepatic stellate cells activation. In addition, alpha smooth muscle-actin as marker of hepatic stellate cells further indicated that TLR5 knockout mice have a lower collagen accumulation in liver tissue than WT mice after carbon tetrachloride administration, resulting in inhibition of NF-κB and MAPK signaling pathways activation. Moreover, in vitro experiment of hepatic stellate cells challenged with LPS or TGF-β, further indicated that NF-κB and MAPK were involved in liver fibrosis development, leading to α-SMA expression and inflammation infiltration. However, cells from TLR5(-)(/-) may weaken phosphorylation levels of signal pathways, finally suppress progress of collagen accumulation and inflammatory responses. These results suggest a new therapeutic approach or target to protect against fibrosis caused by chronic liver diseases.
authors: Department of Hepatobiliary Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China.
authors: Ming
authors: M
authors: Shu
authors: Department of Stem Cell Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China.
authors: Dan-dan
authors: DD
authors: Huang
authors: Department of Stem Cell Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China.
authors: Zuo-an
authors: ZA
authors: Hung
authors: Department of Stem Cell Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China.
authors: Xiao-rong
authors: XR
authors: Hu
authors: Department of Stem Cell Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China. Electronic address: zhangshun315010@163.com.
authors: Shun
authors: S
authors: Zhang
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D051198:Toll-Like Receptor 5; D002251:Carbon Tetrachloride
keywords: Carbon tetrachloride; Hepatic stellate cell; Liver fibrosis; Toll like receptor 5