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Hepatic inflammation mediated by hepatitis C virus core protein is ameliorated by blocking complement activation.

Chang ML, Yeh CT, Lin DY, Ho YP, Hsu CM, Bissell DM - BMC Med Genomics (2009)

Bottom Line: Administration of CD55 reduced hepatic inflammation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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

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.

Aims: 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.

Conclusion: 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.

No MeSH data available.


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Liver histology for 2-old-month DTM with intermediate core expression before (A and C) and after CD55 (B) or PBS (D) injection.
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Figure 6: Liver histology for 2-old-month DTM with intermediate core expression before (A and C) and after CD55 (B) or PBS (D) injection.

Mentions: Of the various proteins identified, the one most closely linked to human hepatitis C is C3 [24]. To probe the functional significance of this association, we studied the effect of a complement pathway inhibitor on HCV core protein-mediated hepatic inflammation. Mice were injected with CD55, which accelerates the decay of C3 convertases in the classical and alternate complement pathways [25]. In DTM with intermediate core expression, the injection of CD55 dramatically reduced hepatic inflammation (Table 4). The mean ALT levels for the transgenic mice 3 days after the CD55 injection were significantly lower than those of the mice that were injected with vehicle alone (179.2 ± 50.92 vs. 654.4 ± 134.51; P < 0.01). The histology of the livers from mice given a CD55 injection also showed fewer infiltrating inflammatory cells compared to mice that received PBS only (Figure 6).


Hepatic inflammation mediated by hepatitis C virus core protein is ameliorated by blocking complement activation.

Chang ML, Yeh CT, Lin DY, Ho YP, Hsu CM, Bissell DM - BMC Med Genomics (2009)

Liver histology for 2-old-month DTM with intermediate core expression before (A and C) and after CD55 (B) or PBS (D) injection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2734540&req=5

Figure 6: Liver histology for 2-old-month DTM with intermediate core expression before (A and C) and after CD55 (B) or PBS (D) injection.
Mentions: Of the various proteins identified, the one most closely linked to human hepatitis C is C3 [24]. To probe the functional significance of this association, we studied the effect of a complement pathway inhibitor on HCV core protein-mediated hepatic inflammation. Mice were injected with CD55, which accelerates the decay of C3 convertases in the classical and alternate complement pathways [25]. In DTM with intermediate core expression, the injection of CD55 dramatically reduced hepatic inflammation (Table 4). The mean ALT levels for the transgenic mice 3 days after the CD55 injection were significantly lower than those of the mice that were injected with vehicle alone (179.2 ± 50.92 vs. 654.4 ± 134.51; P < 0.01). The histology of the livers from mice given a CD55 injection also showed fewer infiltrating inflammatory cells compared to mice that received PBS only (Figure 6).

Bottom Line: Administration of CD55 reduced hepatic inflammation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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

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.

Aims: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus