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, Marc E. Rothenberg

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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.

Original languageEnglish
Article number3244
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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