title: Hepatic inflammation mediated by hepatitis C virus core protein is ameliorated by blocking complement activation.
abstract: BACKGROUND
  The pathogenesis of inflammation and fibrosis in chronic hepatitis C virus (HCV) infection remains unclear. Transgenic mice with constitutive HCV core over-expression display steatosis only. While the reasons for this are unclear, it may be important that core protein production in these models begins during gestation, in contrast to human hepatitis C virus infection, which occurs post-natally and typically in adults.
  
  
  OBJECTIVE
  To more realistically model the effect of core protein production in the adult liver, we developed a mouse with conditional expression of HCV core and examined the effect of core protein production in the adult liver.
  
  
  METHODS
  Liver biopsy samples from transgenic mice with tetracycline(tet)-regulated conditional core protein expression were evaluated immunohistologically. Microarray analysis of HCV core transgenic mice with steatohepatitis pointed to a role of the complement pathway. This was further explored by blocking complement activation by in vivo administration of CD55 (decay accelerating factor for complement), which inhibits activation of C3.
  
  
  RESULTS
  Transgenic mice exhibited low, intermediate, or high HCV core protein expression when fed a permissive diet of standard chow. Aside from hepatic steatosis, hepatic inflammation and fibrosis were seen in mice with intermediate levels of core protein. Microarray analyses of inflamed liver demonstrated activation of both the complement (C3 up-regulation) and coagulation pathways (fibrinogen B up-regulation). Administration of CD55 reduced hepatic inflammation.
  
  
  CONCLUSIONS
  Transgenic mice that conditionally express intermediate HCV core protein develop inflammation, steatosis, and fibrosis. These effects mediated by HCV core are reduced by administration of CD55, a regulator of the complement pathway. The model may be valuable in investigating the pathogenesis of liver inflammation in chronic hepatitis C.
authors: Liver Research Center and Department of Hepatogastroenterology, Chang Gung Memorial Hospital; Chang Gung University, College of Medicine, Taoyuan, Taiwan, Republic of China. mlchang8210@gmail.com
authors: Ming-Ling
authors: ML
authors: Chang
authors: Chau-Ting
authors: CT
authors: Yeh
authors: Deng-Yn
authors: DY
authors: Lin
authors: Yu-Pin
authors: YP
authors: Ho
authors: Chen-Ming
authors: CM
authors: Hsu
authors: D Montgomery
authors: DM
authors: Bissell