Regulation of insulin-like growth factor-I receptor gene expression by tumor necrosis factor-alpha and...

The insulin-like growth factor-I receptor (IGF-l-R) plays a critical role in normal and pathological growth processes. The expression of the IGF-l-R gene is regulated by various stimuli, including hormones and growth factors. We have investigated the molecular mechanisms by which two inhibitory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), regulate IGF-l-R gene expression. TNF-alpha and IFN-gamma reduced the proliferation rates of the osteogenic sarcoma cell line, Saos-2, and the human salivary gland cell line, HSG, in a dose- and time-dependent fashion. This effect was associated with significant reductions in the levels of IGF-l-R mRNA and protein, and with inhibition of IGF-l-R promoter activity, suggesting that TNF-alpha and IFN-gamma affect IGF-l-R gene expression at the transcriptional level. In addition, TNF-alpha significantly decreased IGF-l-R mRNA stability. Combined cytokine treatment inhibited cellular proliferation and promoter activity in an additive manner. Taken together, these results suggest that a novel potential mechanism by which TNF-alpha and IFN-gamma affect cellular proliferation involves suppression of IGF-l-R promoter activity, as well as destabilization of IGF-l-R transcripts.