© 2000 American Heart Association, Inc.
Molecular Medicine |
Interferon-
Induces AT2 Receptor Expression in Fibroblasts by Jak/STAT Pathway and Interferon Regulatory Factor-1
From Cardiovascular Research (M. Horiuchi, J.Y.A.L., K.T., L.D., Y.E.C.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Department of Medical Biochemistry (M. Horiuchi, S.Y., M. Hamai, T.-X.C., M.I., Y.M.), Ehime University School of Medicine, Ehime, Japan; the Department of Medicine (W.H.), Graduate School of Medicine, Kyoto University, Kyoto, Japan; and the Department of Geriatric Medicine (M.A.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp
Abstract—The expression of
angiotensin II type 2 (AT2) receptor is closely
associated with cell growth, differentiation, and/or injury. We
examined the effect of interferon (IFN)-
on AT2 receptor
expression in mouse fibroblast R3T3 cells and demonstrated that IFN-
treatment increased the expression of AT2 receptor mRNA as
well as its binding. Interferon regulatory factor (IRF)-1 was induced
in mouse fibroblast R3T3 cells after IFN- stimulation, and
electrophoretic mobility shift assay showed an increase in IRF-1
binding with the IRF-specific binding sequence in the AT2
receptor gene promoter region after IFN- stimulation. The IRF-1 gene
promoter contains an IFN-–activated sequence (GAS) motif
for possible binding of signal transducer(s) and
activator(s) of transcription (STAT). Indeed, in R3T3
cells, IFN- treatment resulted in rapid activation of Janus kinase
(Jak) 1, Jak2, and STAT1 via tyrosine phosphorylation.
Electrophoretic mobility shift assay with the GAS probe revealed
increased STAT1 binding to the IRF-1 gene promoter in response to
IFN- stimulation. Transfection of GAS-binding
oligonucleotides inhibited the effect of IFN- on
IRF-1 production, resulting in the AT2 receptor
trans-activation. Taken together, our data show that
IFN- upregulates AT2 receptor expression in R3T3 cells
via the activation of the intracellular Jak/STAT pathway and
production of IRF-1.
Key Words: angiotensin • cytokine • receptor • transcription
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