Journal article
Interferon-β and interferon-λ signaling is not affected by interferon-induced refractoriness to interferon-α in vivo.
- Makowska Z Department of Biomedicine, University Basel, Basel, Switzerland.
- Duong FH
- Trincucci G
- Tough DF
- Heim MH
- 2011-04-12
Published in:
- Hepatology (Baltimore, Md.). - 2011
Animals
Cell Line, Tumor
Cytokines
Endopeptidases
Hepatitis C, Chronic
Humans
Interferon Inducers
Interferon-alpha
Interferon-beta
Interferon-gamma
Intestine, Small
Janus Kinases
Liver
Male
Mice
STAT1 Transcription Factor
Signal Transduction
English
UNLABELLED
Therapy of chronic hepatitis C with pegylated interferon α (pegIFN-α) and ribavirin achieves sustained virological responses in approximately half of the patients. Nonresponse to treatment is associated with constitutively increased expression of IFN-stimulated genes in the liver already before therapy. This activation of the endogenous IFN system could prevent cells from responding to therapeutically injected (peg)IFN-α, because prolonged stimulation of cells with IFN-α induces desensitization of the IFN signal transduction pathway. Whether all types of IFNs induce refractoriness in the liver is presently unknown. We therefore treated mice with multiple injections and different combinations of IFN-α, IFN-β, IFN-γ, and IFN-λ. Pretreatment of mice with IFN-α, IFN-β, and IFN-λ induced a strong expression of the negative regulator ubiquitin-specific peptidase 18 in the liver and gut. As a result, IFN-α signaling was significantly reduced when mice where reinjected 16 hours after the first injection. Surprisingly, both IFN-β and IFN-λ could activate the Janus kinase-signal transducer and activator of transcription (STAT) pathway and the expression of IFN-stimulated genes despite high levels of ubiquitin-specific peptidase 18. IFN-λ treatment of human liver biopsies ex vivo resulted in strong and maintained phosphorylation of STAT1, whereas IFN-α-induced STAT1 activation was transient.
CONCLUSION
Contrary to the action of IFN-α, IFN-β, and IFN-λ signaling in the liver does not become refractory during repeated stimulation of the IFN signal transduction pathway. The sustained efficacy of IFN-β and IFN-λ could be an important advantage for the treatment patients who are nonresponders to pegIFN-α, through a preactivated endogenous IFN system.
Therapy of chronic hepatitis C with pegylated interferon α (pegIFN-α) and ribavirin achieves sustained virological responses in approximately half of the patients. Nonresponse to treatment is associated with constitutively increased expression of IFN-stimulated genes in the liver already before therapy. This activation of the endogenous IFN system could prevent cells from responding to therapeutically injected (peg)IFN-α, because prolonged stimulation of cells with IFN-α induces desensitization of the IFN signal transduction pathway. Whether all types of IFNs induce refractoriness in the liver is presently unknown. We therefore treated mice with multiple injections and different combinations of IFN-α, IFN-β, IFN-γ, and IFN-λ. Pretreatment of mice with IFN-α, IFN-β, and IFN-λ induced a strong expression of the negative regulator ubiquitin-specific peptidase 18 in the liver and gut. As a result, IFN-α signaling was significantly reduced when mice where reinjected 16 hours after the first injection. Surprisingly, both IFN-β and IFN-λ could activate the Janus kinase-signal transducer and activator of transcription (STAT) pathway and the expression of IFN-stimulated genes despite high levels of ubiquitin-specific peptidase 18. IFN-λ treatment of human liver biopsies ex vivo resulted in strong and maintained phosphorylation of STAT1, whereas IFN-α-induced STAT1 activation was transient.
CONCLUSION
Contrary to the action of IFN-α, IFN-β, and IFN-λ signaling in the liver does not become refractory during repeated stimulation of the IFN signal transduction pathway. The sustained efficacy of IFN-β and IFN-λ could be an important advantage for the treatment patients who are nonresponders to pegIFN-α, through a preactivated endogenous IFN system.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1002/hep.24189
- PMID 21480323
- Persistent URL
- https://sonar.ch/global/documents/18078
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