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 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.
Maher
Stephen G
SG
Department of Surgery, Trinity College Dublin, Dublin, Ireland.
Sheikh
Faruk
F
Scarzello
Anthony J
AJ
Romero-Weaver
Ana L
AL
Baker
Darren P
DP
Donnelly
Raymond P
RP
Gamero
Ana M
AM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D007372:Interferons; D007378:Interleukins / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D000095022:Interferon Lambda
D000590:Amino Acid Chloromethyl Ketones; D016207:Cytokines; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D053613:Janus Kinase 1; D050794:STAT1 Transcription Factor; D019311:Staurosporine; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494079:STAT1 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone