IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity

Interferon (IFN)lambda, also known as IL-28A, IL-28B or IL-29, is a new type III IFN, which like type I IFN(alpha/beta), activates common elements of the JAK/STAT signaling pathway and exhibits antiproliferative activity. Currently, IFNalpha is used in the treatment of certain forms of cancer, but i...

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Bibliographic Details
Published in:Cancer biology & therapy 2008-07, Vol.7 (7), p.1109
Main Authors: Maher, Stephen G, Sheikh, Faruk, Scarzello, Anthony J, Romero-Weaver, Ana L, Baker, Darren P, Donnelly, Raymond P, Gamero, Ana M
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - pharmacology
Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation
Cytokines - metabolism
Dose-Response Relationship, Drug
Humans
Interferon-alpha - metabolism
Interferons
Interleukins - metabolism
Janus Kinase 1 - metabolism
Kinetics
Mice
Signal Transduction
STAT1 Transcription Factor - metabolism
Staurosporine - pharmacology
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Summary:Interferon (IFN)lambda, also known as IL-28A, IL-28B or IL-29, is a new type III IFN, which like type I IFN(alpha/beta), activates common elements of the JAK/STAT signaling pathway and exhibits antiproliferative activity. Currently, IFNalpha is used in the treatment of certain forms of cancer, but its antitumor effects are limited and associated with high toxicity. In this study, we determined whether IFNlambda induced the same level of cell growth inhibition relative to IFNalpha. To this effect HaCaT cells, which are typically growth inhibited by IFNalpha, underwent apoptosis in response to IFNlambda. Next, in contrast to IFNalpha stimulation, IFNlambda prolonged the duration of activated STAT1 and STAT2. Furthermore, the kinetics of IFN-stimulated genes was different as IFNlambda induced a delayed but stronger induction of IFN-responsive genes. Components of the JAK/STAT pathway remained essential for the antiproliferative effects of IFNalpha and IFNlambda. IFNlambda-induced persistence of STAT activation required de novo protein synthesis and was in part due to a delay in STAT2 inactivation. Thus our data demonstrate that the duration of IFNlambda signaling is different from that of IFNalpha, and that IFNlambda could be a suitable cytokine to evaluate for cancer therapy.
ISSN:1555-8576