Estrogen receptor-mediated modulation of inflammatory markers in hepatitis c virus pathogenesis
Abstract
Hepatitis C virus (HCV) is a global health concern whose pathogenesis depends largely on chronic inflammation; chronic infection with HCV is strongly linked to fibrosis/cirrhosis, liver failure, and hepatocellular carcinoma (HCC). About 80% percent of people infected with HCV will go on to develop chronic infection, and polymorphisms in the IFNL4 gene have been shown to be strong predictors for both clearance as well as response to treatment. Clinical observations have established sex-based differences in HCV infection with the disease progressing more severely and more rapidly in males and postmenopausal females compared to premenopausal females, suggesting that estrogens and their receptors may play an important role in hepatic defenses and development of HCV-mediated cirrhosis and HCC. However, the precise mechanism of estrogen protection is poorly understood. In the current study, the role of ERs in modulating innate immune responses was investigated in vitro using a liver hepatoma (Huh7) cell line, and ex vivo using human liver tissues with HCV/cirrhosis and HCV/HCC. The results of the in vitro experiments revealed that treatment of Huh7 cells with ER agonists (E2 and DPN) and antagonists (ICI) led to changes in expression of ERβ, and inflammatory markers TNFα, CD55, IL-33. These results indicate that estrogens may confer protection in HCV by increasing complement activation (CD55) and decreasing the damaging effects of long-term inflammation (TNFα, IL-33). The lack of response from PPT stimulation indicates that ERβ, not ERα, appears to be the governing ER in liver cells. In the ex vivo study, ERβ was reported for the first time to have a greater mRNA expression than ERα in normal liver. In addition, ERβ mRNA expression was found to be decreased in diseased livers, while TNFα expression was increased. ERβ mRNA expression was also decreased in livers with the IFNL4-ΔG/ΔG genotype. Further analysis of the data revealed sex-specific correlations between ERα and ERβ. All together, these findings indicate that changes in ERβ expression are associated with worsening disease, and may be one of the sex-dependent factors in HCV pathogenesis, particularly the differential interactions of ERα and ERβ between males and females.
Collections
- OSU Dissertations [11222]