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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.


Related in: MedlinePlus

Serum MDA levels for three male DTM with intermediate core expression, three male DTM with high core expression, and three STM in the first month (M1), second month (M2), third month (M3), and fourth month (M4) after one month of DOX withdrawal. Data are expressed as mean ± SD.
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Figure 2: Serum MDA levels for three male DTM with intermediate core expression, three male DTM with high core expression, and three STM in the first month (M1), second month (M2), third month (M3), and fourth month (M4) after one month of DOX withdrawal. Data are expressed as mean ± SD.

Mentions: The livers from all control mice were normal. The pathology for the DTM on permissive chow varied depending on the hepatic level of HCV core protein. Mice with high or low HCV core protein expression showed no significant inflammation (Figures 1A, B, E, and 1F). However, the liver from mice with intermediate HCV core protein expression exhibited an inflammatory infiltrate (Figures 1C and 1D) that was concentrated around hepatocytes displaying the core protein. The plasma MDA level was significantly higher in DTM with intermediate core expression than in DTM with high core expression, and exceeded the levels in STM (Figure 2) and either DTM or STM consuming DOX-containing chow (data not shown).


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)

Serum MDA levels for three male DTM with intermediate core expression, three male DTM with high core expression, and three STM in the first month (M1), second month (M2), third month (M3), and fourth month (M4) after one month of DOX withdrawal. Data are expressed as mean ± SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Serum MDA levels for three male DTM with intermediate core expression, three male DTM with high core expression, and three STM in the first month (M1), second month (M2), third month (M3), and fourth month (M4) after one month of DOX withdrawal. Data are expressed as mean ± SD.
Mentions: The livers from all control mice were normal. The pathology for the DTM on permissive chow varied depending on the hepatic level of HCV core protein. Mice with high or low HCV core protein expression showed no significant inflammation (Figures 1A, B, E, and 1F). However, the liver from mice with intermediate HCV core protein expression exhibited an inflammatory infiltrate (Figures 1C and 1D) that was concentrated around hepatocytes displaying the core protein. The plasma MDA level was significantly higher in DTM with intermediate core expression than in DTM with high core expression, and exceeded the levels in STM (Figure 2) and either DTM or STM consuming DOX-containing chow (data not shown).

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