Interferon-gamma induces AT(2) receptor expression in fibroblasts by Jak/STAT pathway and interferon regulatory factor-1

The expression of angiotensin II type 2 (AT(2)) receptor is closely associa ted with cell growth, differentiation, and/or injury. We examined the effec t of interferon (IFN)-gamma on AT, receptor expression in mouse fibroblast R3T3 cells and demonstrated that IFN-gamma treatment increased the expressi on of AT(2) receptor mRNA as well as its binding. Interferon regulatory fac tor (IRF)-1 was induced in mouse fibroblast R3T3 cells after IFN-gamma stim ulation, and electrophoretic mobility shift assay showed an increase in IRF -1 binding with the IRF-specific binding sequence in the AT, receptor gene promoter region after IFN-gamma stimulation. The IRF-1 gene promoter contai ns an IFN-gamma-activated sequence (GAS) motif for possible binding of sign al transducer(s) and activator(s) of transcription (STAT). Indeed, in R3T3 cells, IFN-gamma treatment resulted in rapid activation of Janus kinase (Ja k) 1, Jak2, and STAT1 via tyrosine phosphorylation. Electrophoretic mobilit y shift assay with the GAS probe revealed increased STAT1 binding to the IR F-1 gene promoter in response to IFN-gamma stimulation. Transfection of GAS -binding oligonucleotides inhibited the effect of IFN-gamma on IRF-1 produc tion, resulting in the AT, receptor trans-activation. Taken together, our d ata show that IFN-gamma upregulates AT, receptor expression in R3T3 cells v ia the activation of the intracellular Jak/STAT pathway and product:ion of IRF-1.