Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells
Version of Record online: 10 DEC 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 1, pages 237–252, January 2014
How to Cite
Lee, J.-C., Tseng, C.-K., Young, K.-C., Sun, H.-Y., Wang, S.-W., Chen, W.-C., Lin, C.-K. and Wu, Y.-H. (2014), Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells. British Journal of Pharmacology, 171: 237–252. doi: 10.1111/bph.12440
- Issue online: 10 DEC 2013
- Version of Record online: 10 DEC 2013
- Accepted manuscript online: 7 OCT 2013 08:50PM EST
- Manuscript Accepted: 24 SEP 2013
- Manuscript Revised: 16 SEP 2013
- Manuscript Received: 17 JUL 2013
- National Science Council of Taiwan. Grant Number: NSC 97-2311-B-037-001-MY3
- National Sun Yat-Sen University-KMU Joint Research Project. Grant Number: NSYSU-KMU 102-I004
- heme oxygenase-1;
- p38 MAPK;
- nuclear factor erythroid 2-related factor 2
Background and Purpose
This study aimed to evaluate the anti-hepatitis C virus (HCV) activity of andrographolide, a diterpenoid lactone extracted from Andrographis paniculata, and to identify the signalling pathway involved in its antiviral action.
Using HCV replicon and HCVcc infectious systems, we identified anti-HCV activity of andrographolide by measuring protein and RNA levels. A reporter activity assay was used to determine transcriptional regulation of anti-HCV agents. A specific inhibitor and short hairpin RNAs were used to investigate the mechanism responsible for the effect of andrographolide on HCV replication.
In HCV replicon and HCVcc infectious systems, andrographolide time- and dose-dependently suppressed HCV replication. When combined with IFN-α, an inhibitor targeting HCV NS3/4A protease (telaprevir), or NS5B polymerase (PSI-7977), andrographolide exhibited a significant synergistic effect. Andrographolide up-regulated the expression of haeme oxygenase-1 (HO-1), leading to increased amounts of its metabolite biliverdin, which was found to suppress HCV replication by promoting the antiviral IFN responses and inhibiting NS3/4A protease activity. Significantly, these antiviral effects were attenuated by an HO-1-specific inhibitor or HO-1 gene knockdown, indicating that HO-1 contributed to the anti-HCV activity of andrographolide. Andrographolide activated p38 MAPK phosphorylation, which stimulated nuclear factor erythroid 2-related factor 2 (Nrf2)–mediated HO-1 expression, and this was found to be associated with its anti-HCV activity.
Conclusions and Implications
Our results demonstrate that andrographolide has the potential to control HCV replication and suggest that targeting the Nrf2–HO-1 signalling pathway might be a promising strategy for drug development.