Potential conflict of interest: Nothing to report.
Liver Failure/Cirrhosis/Portal Hypertension
Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis
Article first published online: 27 MAY 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 1, pages 237–249, July 2014
How to Cite
Roh, Y. S., Park, S., Kim, J. W., Lim, C. W., Seki, E. and Kim, B. (2014), Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis. Hepatology, 60: 237–249. doi: 10.1002/hep.26981
Supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0064313), (2010-0003644), by the Brain Korea 21 Plus Program in 2013, Republic of Korea, and NIH/NIDDK R01DK085252 and NIH/NIEHS P42ES010337 (to Ekihiro Seki).
- Issue published online: 26 JUN 2014
- Article first published online: 27 MAY 2014
- Accepted manuscript online: 21 DEC 2013 12:32AM EST
- Manuscript Accepted: 6 DEC 2013
- Manuscript Received: 20 NOV 2012
Toll-like receptor 7 (TLR7) signaling predominantly regulates production of type I interferons (IFNs), which has been suggested in clinical studies to be antifibrotic. However, the mechanistic role of the TLR7-type I IFN axis in liver fibrosis has not been elucidated. In the present study, liver fibrosis was induced in wild-type (WT), TLR7-deficient, and IFN-α/β receptor-1 (IFNAR1)-deficient mice and TLR7-mediated signaling was assessed in liver cells isolated from these mice. TLR7-deficient and IFNAR1-deficient mice were more susceptible to liver fibrosis than WT mice, indicating that TLR7-type I IFN signaling exerts a protective effect against liver fibrosis. Notably, the hepatic expression of interleukin-1 receptor antagonist (IL-1ra) was suppressed in TLR7- or IFNAR1-deficient mice compared with respective WT mice, and treatment with recombinant IL-1ra reduced liver fibrosis. In vivo activation of TLR7 significantly increased IFNa4 and IL-1ra expression in the liver. Interestingly, each cytokine had a different cellular source, showing that dendritic cells (DCs) are the responsible cell type for production of type I IFN, while Kupffer cells (KCs) mainly produce IL-1ra in response to type I IFN. Furthermore, TLR7 activation by R848 injection suppressed liver fibrosis and production of proinflammatory cytokines, and these effects were dependent on type I IFN signaling. Consistent with in vivo data, IFN-α significantly induced IL-1ra production in primary KCs. Conclusion: TLR7 signaling activates DCs to produce type I IFN, which in turn induces antifibrogenic IL-1ra production in KCs. Thus, manipulation of the TLR7-type I IFN-IL-1ra axis may be a new therapeutic strategy for the treatment of liver fibrosis. (Hepatology 2014;60:237–249)