Chromatin regulates IL-33 release and extracellular cytokine activity

Jared Travers, Mark Rochman, Cora E. Miracle, Jeff E. Habel, Michael Brusilovsky, Julie M. Caldwell, Jeffrey K. Rymer and Marc E. Rothenberg ()
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Jared Travers: Cincinnati Children’s Hospital Medical Center
Mark Rochman: Cincinnati Children’s Hospital Medical Center
Cora E. Miracle: Cincinnati Children’s Hospital Medical Center
Jeff E. Habel: Cincinnati Children’s Hospital Medical Center
Michael Brusilovsky: Cincinnati Children’s Hospital Medical Center
Julie M. Caldwell: Cincinnati Children’s Hospital Medical Center
Jeffrey K. Rymer: Cincinnati Children’s Hospital Medical Center
Marc E. Rothenberg: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05485-x

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