title: Protective effects of a novel trimerized sTNFRII on acute liver injury.
abstract: TNF α plays a central role in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and murine acute liver injury induced by injection of D-galactosamine and subsequent LPS. Recombinant Fc-fused soluble TNF receptor II (sTNFRII-Fc) has been used in the treatment of rheumatoid arthritis for a decade. We have recently constructed a novel fusion protein sTNFRII-gAD, which is composed of a soluble TNF receptor II and a globular domain of adiponectin. Utilizing the inclination of gAD to form homologous trimer naturally, we sought to explore TNFα antagonism of the novel trimerized sTNFRII-gAD and meantime compare TNFα-neutralizing effects in vitro and in vivo between sTNFRII-Fc and sTNFRII-gAD. Here, we evaluated the TNFα-antagonizing activity of sTNFRII-gAD with TNFα-induced L929 cytotoxicity assay. Furthermore, sTNFRII-Fc or sTNFRII-gAD was administered simultaneously with d-galactosamine 1h prior to LPS injection in the murine model of acute liver injury. Serum TNFα and TNFα-sTNFRII-gAD complex were measured by ELISA and the liver injury was assessed through alanine transaminase measurement and liver histological analysis. sTNFRII-gAD was shown to have higher TNFα-neutralizing activity than sTNFRII-Fc (p<0.05) in the L929 cytotoxicity assay. With a significant attenuation of murine lethality (p<0.05), sTNFRII-gAD showed more protective effects than sTNFRII-Fc in the murine model of acute liver injury. These results demonstrated that sTNFRII-gAD was more efficacious than sTNFRII-Fc as a TNFα antagonist, highlighting the potential of sTNFRII-gAD for the treatment of diseases associated with excessive TNFα.
authors.affiliation: School of Biotechnology, Southern Medical University, Guangzhou, China; Department of Microbiology & Immunology, Jinggangshan University, Jian, China.
authors.forename: Mansheng
authors.initials: M
authors.lastname: Luo
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Lingmin
authors.initials: L
authors.lastname: Zhang
authors.forename: Shigao
authors.initials: S
authors.lastname: Huang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Tong
authors.initials: T
authors.lastname: Cui
authors.forename: Honghui
authors.initials: H
authors.lastname: Ma
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.forename: Chunhui
authors.initials: C
authors.lastname: Xiong
authors.forename: Jianhong
authors.initials: J
authors.lastname: Zhu
authors.forename: Jinlong
authors.initials: J
authors.lastname: Li
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wu
authors.forename: Liqin
authors.initials: L
authors.lastname: Jin
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Hu
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D052242:Adiponectin / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use*; D012995:Solubility; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D052242:Adiponectin; D008070:Lipopolysaccharides; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5