Abstract
IL-33 is an epithelium-derived, pro-inflammatory alarmin with enigmatic nuclear localization and chromatin binding. Here we report the functional properties of nuclear IL-33. Overexpression of IL-33 does not alter global gene expression in transduced epithelial cells. Fluorescence recovery after photobleaching data show that the intranuclear mobility of IL-33 is ~10-fold slower than IL-1α, whereas truncated IL-33 lacking chromatin-binding activity is more mobile. WT IL-33 is more resistant to necrosis-induced release than truncated IL-33 and has a relatively slow, linear release over time after membrane dissolution as compared to truncated IL-33 or IL-1α. Lastly, IL-33 and histones are released as a high-molecular weight complex and synergistically activate receptor-mediated signaling. We thus propose that chromatin binding is a post-translational mechanism that regulates the releasability and ST2-mediated bioactivity of IL-33 and provide a paradigm to further understand the enigmatic functions of nuclear cytokines.
Highlights
IL-33 is an epithelium-derived, pro-inflammatory alarmin with enigmatic nuclear localization and chromatin binding
Much attention has been focused on IL-33, an IL-1 family member expressed by mucosal epithelial cells[3,4], because it is a potent alarmin, capable of initiating acute inflammation and priming for type 2 immune responses[5,6]
Using immunofluorescence with two different antibodies directed against IL-33, only nuclear expression was detected in esophageal epithelial cells in biopsies derived from patients with eosinophilic esophagitis (EoE) (Supplementary Fig. 1A, B)
Summary
IL-33 is an epithelium-derived, pro-inflammatory alarmin with enigmatic nuclear localization and chromatin binding. IL-33 and histones are released as a high-molecular weight complex and synergistically activate receptor-mediated signaling. We propose that chromatin binding is a post-translational mechanism that regulates the releasability and ST2-mediated bioactivity of IL-33 and provide a paradigm to further understand the enigmatic functions of nuclear cytokines. Several other nucleosome acidic patch-binding proteins act as transcriptional regulators[23], including high mobility group N2 (HMGN2) and latencyassociated nuclear antigen (LANA) of the Kaposi sarcoma herpesvirus. We aimed to define the functional significance of the nuclear localization and chromatin binding of IL-33 in epithelial cells. We propose that chromatin binding is a post-translational mechanism that regulates the releasability and ST2-mediated bioactivity of IL-33. We propose the paradigm that nuclear localization of cytokines provides a means for fine-tune regulation of cytokine release, availability and activity
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