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J. Biol. Chem. 287 (9): 6941-6948

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Conflicting data describe Interleukin 33 as a nuclear factor and ligand for a transmembrane receptor complex.

Results: IL-33 displays multi-compartmental geography, inter-organelle flux and extracellular release from mechanically stressed cells.

Conclusion: IL-33 manifests dynamic subcellular mobility and secretion from living cells upon biomechanical strain.

Significance: IL-33 belongs to a group of factors displaying dual inflammatory and mechano-responsive properties.

Interleukin 33 as a Mechanically Responsive Cytokine Secreted by Living Cells*Formula

Rahul Kakkar{ddagger}§, Hillary Hei{ddagger}, Stephan Dobner{ddagger}, , and Richard T. Lee{ddagger}1

From the {ddagger}Department of Medicine, Harvard Stem Cell Institute and the Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139 and
the §Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts 02114

ABSTRACT Back to Top

Abstract: Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.

Key Words: Cytokine • Fibroblast • Innate Immunity • Interleukin • Protein Secretion • Alarmin • Paracrine

Received for publication August 29, 2011. Revision received December 22, 2011.

1 To whom correspondence should be addressed: Partners Research Facility, 65 Landsdowne St., Cambridge, MA 02139. Tel.: 617-768-8282; Fax: 617-768-8270; E-mail: RLee{at}

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