Article first published online: 14 MAR 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 4, pages 1314–1324, April 2013
How to Cite
Lee, H.-C., Sung, S.-S. J., Krueger, P. D., Jo, Y.-A., Rosen, H. R., Ziegler, S. F. and Hahn, Y. S. (2013), Hepatitis C virus promotes t-helper (Th)17 responses through thymic stromal lymphopoietin production by infected hepatocytes. Hepatology, 57: 1314–1324. doi: 10.1002/hep.26128
Potential conflict of interest: Dr. Ziegler owns stock in Amgen.
Supported by NIH grants AI098126 to Y.S.H.; U19AI066328 to H.R., Y.S.H.; U19AI083024 to S.J.S.
- Issue published online: 8 APR 2013
- Article first published online: 14 MAR 2013
- Accepted manuscript online: 13 NOV 2012 11:01PM EST
- Manuscript Accepted: 23 OCT 2012
- Manuscript Received: 10 AUG 2012
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Here we report that infection of hepatic cells by HCV stimulates nuclear factor kappa B (NFκB)-dependent production of thymic stromal lymphopoietin (TSLP). Hepatocyte-derived TSLP in turn conditions dendritic cells (DCs) to drive T-helper (Th)17 differentiation. The TSLP secreted by HCV-infected hepatoma cells is capable of activating human monocyte-derived DCs by up-regulating the expression of CD40, CD86, CCL17, CCL22, and CCL20 which are activating markers of DCs. In addition, the production of key cytokines for Th17 differentiation, transforming growth factor beta (TGF-β), interleukin (IL)-6, and IL-21, is enhanced by human monocytes upon coculture with HCV-infected cells. Importantly, the blockade of TSLP using neutralizing antibody prevented the activation and maturation of DCs as well as the production of Th17 differentiation cytokines. DC conditioning by TSLP secreted from HCV-infected cells activated naïve CD4+ T lymphocytes, resulting in Th17 differentiation. Furthermore, we can detect substantial levels of hepatocyte TSLP in fibrotic liver tissue from chronic HCV patients. Thus, blockade of TSLP released by HCV-infected hepatocytes may suppress the induction/maintenance of hepatic Th17 responses and halt the progression of chronic liver disease to fibrosis and liver failure. Conclusion: Hepatocyte-derived TSLP conditions DCs to drive Th17 differentiation. Treatment of TSLP neutralizing antibody in HCV-infected hepatocyte/DC coculture abrogates DC conditioning and thereby inhibits Th17 differentiation. (HEPATOLOGY 2013)