The Dual Function Cytokine IL-33 Interacts with the Transcription Factor NF-κB To Dampen NF-κB-Stimulated Gene Transcription

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-kappa B. This interaction occurs between the N-terminal part of IL-33 from aa 66-109 and the N-terminal Rel homology domain of NF-kappa B p65. Coimmunoprecipitation experiments in cells overexpressing IL-33 or endogenously expressing IL-33 revealed rhIL-1 beta-stimulated association between IL-33 and p65, whereas binding to the p50 subunit was constitutive. The biological consequence of IL-33/NF-kappa B complex formation was reduction in NF-kappa B 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-1 beta-stimulated expression of endogenous NF-kappa B target genes such as I kappa B alpha, TNF-alpha, and C-REL. We suggest that nuclear IL-33 sequesters nuclear NF-kappa B and reduces NF-kappa B-triggered gene expression to dampen proinflammatory signaling. The Journal of Immunology, 2011, 187: 1609-1616.