title: Regulation of NF-κB-dependent gene expression by ligand-induced endocytosis of the interleukin-1 receptor.
abstract: 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.
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hansen
authors.forename: Oliver
authors.initials: O
authors.lastname: Dittrich-Breiholz
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.forename: Mark
authors.initials: M
authors.lastname: Windheim
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006835:Hydrazones; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D008024:Ligands; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D034281:Dynamins