Interferon-γ Induces AT 2 Receptor Expression in Fibroblasts by Jak/STAT Pathway and Interferon Regulatory Factor-1

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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)-γ on AT2 receptor expression in mouse fibroblast R3T3 cells and demonstrated that IFN-γ 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-γ 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-γ stimulation. The IRF-1 gene promoter contains an IFN-γ–activated sequence (GAS) motif for possible binding of signal transducer(s) and activator(s) of transcription (STAT). Indeed, in R3T3 cells, IFN-γ 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-γ stimulation. Transfection of GAS-binding oligonucleotides inhibited the effect of IFN-γ on IRF-1 production, resulting in the AT2 receptor trans-activation. Taken together, our data show that IFN-γ upregulates AT2 receptor expression in R3T3 cells via the activation of the intracellular Jak/STAT pathway and production of IRF-1.

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