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

The insulin-like growth factor-I receptor (IGF-1-R) plays a critical role i n normal and pathological growth processes. The expression of the IGF-1-R g ene is regulated by various stimuli, including hormones and growth factors. We have investigated the molecular mechanisms by which two inhibitory cyto kines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-ga mma), regulate IGF-1-R gene expression. TNF-alpha and IFN-gamma reduced the proliferation rates of the osteogenic sarcoma cell line, Saos-2, and the h uman salivary gland cell line, HSG, in a dose- and time-dependent fashion. This effect was associated with significant reductions in the levels of IGF -I-R mRNA and protein, and with inhibition of IGF-I-R promoter activity, su ggesting that TNF-alpha and IFN-gamma affect IGF-I-R gene expression at the transcriptional level. In addition, TNF-alpha significantly decreased IGF- I-R mRNA stability. Combined cytokine treatment inhibited cellular prolifer ation and promoter activity in an additive manner. Taken together, these re sults suggest that a novel potential mechanism by which TNF-alpha and IFN-g amma affect cellular proliferation involves suppression of IGF-I-R promoter activity, as well as destabilization of IGF-1-R transcripts. (C) 2001 Else vier Science Ireland Ltd. All rights reserved.