NFκB mediates IL‐1β‐induced down‐regulation of TβRII through the modulation of Sp3 expression

• Published in: Journal of cellular and molecular medicine 2008-09, Vol.12 (5a), p.1754-1766
• Main Authors: Baugé, C., Beauchef, G., Leclercq, S., Kim, S. J., Pujol, J. P., Galéra, P., Boumédiene, K.
• Format: Article
• Language: English
• Subjects: Biotechnology; Down-regulation; Experiments; Genes; IL-1β; interleukin‐1; Kinases; NF-κB protein; NFκB; Oligonucleotides; Plasmids; Protein biosynthesis; Sp transcription factors; Sp1 protein; TGFß receptors; Transcription factors
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2007.00173.x

We previously showed that interleukin‐1β (IL‐1β) down‐regulation of type II TGFβ receptor (TβRII) involves NFκB pathway and requires de novo synthesis of a yet unknown protein. Here, we demonstrate that this effect is mediated through Sp1 site located at position ‐25 of human TβRII promoter. Inhibition of transcription factors binding (decoy oligonucleotides or mithramycin) abolished IL‐1β effect. EMSA and ChIP revealed that this treatment induced Sp3 binding to cis‐sequence whereby IL‐1β exerts its transcriptional effects whereas it decreased that of Sp1. Moreover, although the cytokine did not modulate Sp1 expression, it increased that of Sp3 via NFκB pathway. Experiments of gain and loss of function clearly showed that Sp3 inhibited TβRII expression whereas its silencing abolished IL‐1β effect. In addition, both Sp1 and Sp3 were found to interact with NFκB, which therefore may indirectly interact with TβRII pro moter. Altogether, these data suggest that IL‐1β decreases TβRII expression by inducing Sp3 via NFκB and its binding on core promote at the expense of Sp1, which could explain the loss of cell responsiveness in certain conditions. These findings bring new insights in the knowledge of the interference between two antagonistic transduction pathways involved in multiple physiopathological processes.