Regulation of NF-κB-dependent gene expression by ligand-induced endocytosis of the interleukin-1 receptor.

Interleukin-1 (IL-1) induces the internalization of its cognate receptor from the plasma membrane. However, it has remained elusive as to how this mechanism affects the IL-1-induced signal transduction. In this study, we used small-molecule inhibitors of receptor endocytosis to analyze the effects on IL-1-induced signal transduction pathways. We demonstrate that the inhibition of endocytosis down-modulates IL-1-induced NF-κB-dependent gene expression at a level downstream of nuclear translocation and DNA binding of NF-κB. Moreover, we report that the reduced NF-κB-dependent gene expression disrupts feedback inhibition loops terminating the activation of mitogen-activated protein kinases and down-regulating the expression of IL-1-induced mRNAs. Collectively, we show that the inhibition of endocytosis causes a dysregulation of IL-1-induced signal transduction and gene expression demonstrating an important role for receptor internalization in IL-1 signaling.