These authors contributed equally to this work.
Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression
Article first published online: 18 FEB 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 4, pages 1262–1272, April 2014
How to Cite
Bolen, C. R., Ding, S., Robek, M. D. and Kleinstein, S. H. (2014), Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. Hepatology, 59: 1262–1272. doi: 10.1002/hep.26657
See Editorial on Page 1225
Potential conflict of interest: Nothing to report.
Partially funded by NIH NIDDK grant: Silvio O. Conte Digestive Diseases Research Core Centers, grant number: P30 DK034989. The work of C.R.B. was supported in part by NIH grant T15 LM07056 from the National Library of Medicine. S.D. was supported in part by a fellowship from the China Scholarship Council.
- Issue published online: 24 MAR 2014
- Article first published online: 18 FEB 2014
- Accepted manuscript online: 8 AUG 2013 08:17AM EST
- Manuscript Accepted: 22 JUL 2013
- Manuscript Received: 1 APR 2013
Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize virus replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, clustering and promoter analyses of microarray-based gene expression profiling were combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-β > IFN-α > IFN-λ3 > IFN-λ1 > IFN-λ2). Notably, although the hierarchy identified varying numbers of differentially expressed genes when quantified using common statistical thresholds, further analysis of gene expression over multiple timepoints indicated that the individual IFNs do not in fact regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-α. While stimulation with either IFN-β or IFN-λs resulted in a similar long-lasting ISG induction, IFN-α signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-α reveal potential specific roles for individual IFNs in the immune response, and elucidate the mechanism behind previously observed differences in IFN antiviral activity. While current clinical trials are focused on IFN-λ1 as a potential antiviral therapy, the finding that IFN-λ3 invariably possesses the highest activity among type III IFNs suggests that this cytokine may have superior clinical activity. (Hepatology 2014;59:1262-1272)