Protective effects of a novel trimerized sTNFRII on acute liver injury

• Published in: International immunopharmacology 2012-05, Vol.13 (1), p.88-92
• Main Authors: Luo, Mansheng, Liu, Dan, Zhang, Lingmin, Huang, Shigao, Yang, Wenjuan, Zhang, Lin, Cui, Tong, Ma, Honghui, Wang, Zhen, Sun, Qian, Xiong, Chunhui, Zhu, Jianhong, Li, Jinlong, Wu, Xiaobing, Jin, Liqin, Hu, Zhiming, Gao, Jimin
• Format: Article
• Language: English
• Subjects: Acute liver injury; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Acute Lung Injury - prevention & control; Adiponectin; Adiponectin - biosynthesis; Adiponectin - blood; Adiponectin - therapeutic use; Alanine transaminase; Animal models; Animals; Biological and medical sciences; Cell Line, Tumor; Cell Survival; CHO Cells; Cricetinae; Cricetulus; Cytotoxicity; D-Galactosamine; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Fusion protein; Inflammatory diseases; Injuries; Lethality; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Liver; LPS; Medical sciences; Mice; Mice, Inbred BALB C; Pharmacology. Drug treatments; Receptors, Tumor Necrosis Factor, Type II - biosynthesis; Receptors, Tumor Necrosis Factor, Type II - blood; Receptors, Tumor Necrosis Factor, Type II - therapeutic use; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - blood; Recombinant Fusion Proteins - therapeutic use; Rheumatoid arthritis; Solubility; sTNFR; Survival Analysis; TNFα antagonist; Tumor necrosis factor; Tumor necrosis factor receptors; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - blood
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2012.03.013

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