title: NLRC5 regulates TGF-β1-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis.
abstract: Therapeutic management of liver fibrosis remains an unsolved clinical problem. Hepatic accumulation of extracellular matrix, mainly collagen, is mediated by the production of transforming growth factor-β1 (TGF-β1) in hepatic stellate cells (HSCs). NLRC5, the largest member of the NLR protein family, has recently been identified as a critical regulator of immune responses. Novel evidence shows that NLRC5 is an important negative modulator of inflammatory pathways. Herein, we determined the regulation of NLRC5 in liver fibrogenesis and its underlying mechanisms. We have shown that NLRC5 was upregulated in human liver fibrotic tissues. Overexpression of NLRC5 resulted in an upregulation of collagen 1 and α-smooth muscle actin expression in HSC LX-2 cells, which was inhibited by NLRC5 knockdown with its siRNA. Furthermore, NLRC5 deficiency significantly suppressed TGF-β1-induced proliferation but increased apoptosis (i.e., increased caspases-3, DR4 and DR5) in LX-2 cells. In addition, knockdown of NLRC5 promoted the activation of NF-κB signaling pathways but abrogated phosphorylation of Smad2 and Smad3 proteins in response to TGF-β1. These results indicate that NLRC5 is a potent pro-fibrogenic molecule for HSC activation through TGF-β1/Smad and NF-κB signaling pathways. NLRC5 inhibition would be a promising therapeutic avenue for treating hepatic fibrosis.
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
authors.forename: Ming-ming
authors.initials: MM
authors.lastname: Ni
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
authors.lastname: Xing-Li
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiao-feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei 230032, China. Electronic address: lj@ahmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; C105190:TNFRSF10A protein, human; D053773:Transforming Growth Factor beta1; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Hepatic stellate cell; Liver fibrosis; NF-κB; NLR; NLRC5; Smad