Chromatin regulates IL-33 release and extracellular cytokine activity

• DOI: 10.1038/s41467-018-05485-x
• Publication Date: 2018-08-08T08:11:46Z
• Authors: Jared Travers; Mark Rochman; Cora E. Miracle; Jeff E. Habel; Michael Brusilovsky; Julie M. Caldwell; Jeffrey K. Rymer; Marc E. Rothenberg
• Keywords: Cell Nucleus; 0301 basic medicine; Science; Q; Interleukin-33; Interleukin-1 Receptor-Like 1 Protein; Models, Biological; Article; Chromatin; Cell Line; Histones; Kinetics; Necrosis; 03 medical and health sciences; Gene Expression Regulation; Heterochromatin; Cytokines; Humans; Extracellular Space; Protein Binding

AbstractIL-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.