Tumor Necrosis Factor α Inhibits Transcriptional Activity of the Porcine P-45011A Insulin-like Growth Factor Response Element

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We investigated the effects of tumor necrosis factor alpha (TNFalpha) on the transcriptional activity of the porcine P-45011A (P450scc) insulin-like growth factor response element (IGFRE). TNFalpha inhibited insulin-like growth factor-I (IGF-I)-stimulated P450scc mRNA concentrations in cultures of porcine granulosa cells. Transient transfection experiments in granulosa cells with deletion P450scc/luciferase constructs showed that TNFalpha inhibited the transcriptional activity of the IGFRE. IGF-I binding and IGF-I receptor mRNA concentrations in porcine granulosa cells were not inhibited by TNFalpha. Electrophoretic mobility shift assay with nuclear extract protein from porcine granulosa cells treated with IGF-I and TNFalpha showed that Sp1 and a second transcription factor, P2, bound to the IGFRE. While IGF-I treatment increased the binding activity of both factors, TNFalpha specifically inhibited the IGF-I-stimulated binding activity of P2. Transient transfection studies done in mouse fibroblasts overexpressing the IGF-I receptor (NWTb3) with the porcine IGFRE (three repeats) in an SV40/luciferase construct also showed TNFalpha inhibited IGF-I-stimulated reporter gene expression. We conclude that TNFalpha inhibits the transcriptional activity of the porcine P450scc IGFRE by preventing IGF-I-stimulated binding of P2.