Critical role for constitutive type I interferon signaling in the prevention of cellular transformation.
Interferons-alpha/beta, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN-alpha/beta show a preventive role in cellular transformation. Ifnar1-deficient (Ifnar1(-/-)) MEF, which are devoid of IFN-alpha/beta signal, undergo a spontaneous transformation during long-term cell culture. Similar to Irf1(-/-) MEF, primary Ifnar1(-/-) MEF become tumorigenic in nude mice by the expression of activated c-Ha-Ras oncoprotein. However, Ifnar1(-/-) MEF do not show any abnormal growth properties. A similar observation is made in Ifnb(-/-) MEF that fail to produce constitutive IFN-alpha/beta, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1(-/-) mice develop chemically-induced skin papilloma more severely than wild-type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell-intrinsic role of the weak signal by constitutively produced IFN-alpha/beta to prevent cells from transformation, which may be mediated by a hitherto-unknown pathway(s) downstream of the IFN-alpha/beta receptor.
Chen
Hui-Min
HM
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Tanaka
Nobuyuki
N
Mitani
Yukiko
Y
Oda
Eri
E
Nozawa
Hiroaki
H
Chen
Jian-Zhong
JZ
Yanai
Hideyuki
H
Negishi
Hideo
H
Choi
Myoung Kwon
MK
Iwasaki
Toshiroh
T
Yamamoto
Hiroyuki
H
Taniguchi
Tadatsugu
T
Takaoka
Akinori
A
D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics
D002273:Carcinogens; C507964:IFNAR1 protein, human; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta