title: The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription.
abstract: Full-length IL-33 is a member of the IL-1 family of cytokines, which can act in an autocrine or paracrine manner by binding to the IL-33R on several different target cell types. In addition, IL-33 can act in an intracrine fashion by translocating to the nucleus, where it binds to the chromatin and modulates gene expression. In this article, we report that full-length IL-33, but not mature IL-33, interacts with the transcription factor NF-κB. This interaction occurs between the N-terminal part of IL-33 from aa 66-109 and the N-terminal Rel homology domain of NF-κB p65. Coimmunoprecipitation experiments in cells overexpressing IL-33 or endogenously expressing IL-33 revealed rhIL-1β-stimulated association between IL-33 and p65, whereas binding to the p50 subunit was constitutive. The biological consequence of IL-33/NF-κB complex formation was reduction in NF-κB p65 binding to its cognate DNA and impairment of p65-triggered transactivation. Overexpression of IL-33 resulted in a reduction and delay in the rhIL-1β-stimulated expression of endogenous NF-κB target genes such as IκBα, TNF-α, and C-REL. We suggest that nuclear IL-33 sequesters nuclear NF-κB and reduces NF-κB-triggered gene expression to dampen proinflammatory signaling.
authors: Department of Immunology, FB 08, Justus-Liebig-University, 35394 Giessen, Germany.
authors: Shafaqat
authors: S
authors: Ali
authors: Antje
authors: A
authors: Mohs
authors: Meike
authors: M
authors: Thomas
authors: Jan
authors: J
authors: Klare
authors: Ralf
authors: R
authors: Ross
authors: Michael Lienhard
authors: ML
authors: Schmitz
authors: Michael Uwe
authors: MU
authors: Martin
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*
chemical_list: C506536:IL33 protein, human; C506535:Il33 protein, mouse; D020382:Interleukin-18; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C073701:Nfkb1 protein, mouse