IGF-1 down-regulates IFN- R2 chain surface expression and desensitizes IFN- /STAT-1 signaling in human T lymphocytes

The ability of insulin-like growth factor-1 (IGF-1) to regulate surface expression of the interferonreceptor 2 (IFNR2) transducing chain and activation of IFN– induced signal transducer and activator of transcription-1 (STAT-1) in human T cells was analyzed. We show that, especially in the absence of serum (which contains IGF-1), IGF-1 down-regulated surface expression of the IFNR2 chain and inhibited both IFN–dependent STAT-1 activation and apoptosis in T-cell lines ST4, Jurkat, and Molt-4. IFNR2 down-regulation resulted from its enhanced internalization since IGF-1 completely restored the uptake of anti–IFNR2 monoclonal antibody (mAb) in serumdeprived T-cell lines. When the interaction between IGF-1 and its receptor was blocked by anti–IGF-1R mAb, enhancement of IFNR2 surface expression, STAT-1 activation, and reinstatement of IFN–induced apoptosis were observed. Enhanced expression of IFNR2 was also observed in phytohemagglutinin (PHA)– activated T lymphoblasts cultured in the presence of anti–IGF-1R mAb, whereas IGF-1 or anti–IGF-1R mAb did not modify the high IFNR2 expression in B and myeloid cell lines. Both IGF-1 and anti– IGF-1R mAb did not modify the constitutive expression of IFNR2 mRNA in T cells as well as the high IFNR1 binding chain surface expression in T, B, and myeloid cells. These data indicate that IGF-1 plays a critical role in the desensitization of IFN/STAT-1 signaling in T lymphocytes by delivering a signal for IFNR2 internalization. (Blood. 2003;102: 2933-2939)