IGF-1 down-regulates IFN-gamma R2 chain surface expression and desensitizes IFN-gamma/STAT-1 signaling in human T lymphocytes.
The ability of insulin-like growth factor-1 (IGF-1) to regulate surface expression of the interferon-gamma receptor 2 (IFN-gamma R2) transducing chain and activation of IFN-gamma-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 IFN-gamma R2 chain and inhibited both IFN-gamma-dependent STAT-1 activation and apoptosis in T-cell lines ST4, Jurkat, and Molt-4. IFN-gamma R2 down-regulation resulted from its enhanced internalization since IGF-1 completely restored the uptake of anti-IFN-gamma R2 monoclonal antibody (mAb) in serum-deprived T-cell lines. When the interaction between IGF-1 and its receptor was blocked by anti-IGF-1R mAb, enhancement of IFN-gamma R2 surface expression, STAT-1 activation, and reinstatement of IFN-gamma-induced apoptosis were observed. Enhanced expression of IFN-gamma R2 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 IFN-gamma R2 expression in B and myeloid cell lines. Both IGF-1 and anti-IGF-1R mAb did not modify the constitutive expression of IFN-gamma R2 mRNA in T cells as well as the high IFN-gamma R1 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-gamma/STAT-1 signaling in T lymphocytes by delivering a signal for IFN-gamma R2 internalization.
Bernabei
Paola
P
Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, and Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
Bosticardo
Marita
M
Losana
Giuliana
G
Regis
Gabriella
G
Di Paola
Francesca
F
De Angelis
Stefania
S
Giovarelli
Mirella
M
Novelli
Francesco
F
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D003470:Culture Media / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D005434:Flow Cytometry; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010835:Phytohemagglutinins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D003470:Culture Media; D004268:DNA-Binding Proteins; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human