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

We previously showed that interleukin-1 beta (IL-1 beta) down-regulation of type II TGF beta receptor (T beta RII) involves NF kappa B 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 T beta RII promoter. Inhibition of transcription factors binding (decoy oligonucleotides or mithramycin) abolished IL-1 beta effect. EMSA and ChIP revealed that this treatment induced Sp3 binding to cis-sequence whereby IL-1 beta 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 NF kappa B pathway. Experiments of gain and loss of function clearly showed that Sp3 inhibited T beta RII expression whereas its silencing abolished IL-1 beta effect. In addition, both Sp1 and Sp3 were found to interact with NF kappa B, which therefore may indirectly interact with T beta RII promoter. Altogether, these data suggest that IL-1 beta decreases T beta RII expression by inducing Sp3 via NF kappa B 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.