Insulin-like growth factor-1 downregulates nuclear factor κB activation and upregulates interleukin-8 gene expression induced by tumor necrosis factor α

Pretreatment of HT29-D4 epithelial adenocarcinoma colic cells with des-IGF-1 upregulated TNFalpha-mediated activation of IL-8 expression at different levels (protein, mRNA, and hnRNA). RNA transcription but not RNA stabilization was found to be involved. In this cell line, cooperation of NF-kappaB with other factors appeared essential for IL-8 expression. Indeed, TNFalpha-induced NF-kappaB translocation was not sufficient to support enhancement of the transcription and des-IGF-1 did not promote but partly inhibited both the TNFa-induced NF-kappaB activation and IkappaBalpha degradation through a PI-3K-dependent pathway. A CCAAT/enhancer binding protein (C/EBP) site located on the IL-8 gene enhancer cooperated with a NF-kappaB binding site and led to the upregulation of IL-8 expression. Binding of C/EBPalpha to this sequence disappeared in IGF-1 treated cells. This event may be important for the crosstalk between IGF-1- and TNFalpha-mediated pathways leading to the control of inflammatory processes and the decision concerning apoptosis or cell survival. (C) 2003 Elsevier Science (USA). All rights reserved.