Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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}partners.org.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-{kappa}B and ERK1/2 signaling.
W.-T. Hu, M.-Q. Li, W. Liu, L.-P. Jin, D.-J. Li, and X.-Y. Zhu (2014)
Mol. Hum. Reprod. 20, 358-372
   Abstract »    Full Text »    PDF »
Alarmin IL-33 Acts as an Immunoadjuvant to Enhance Antigen-Specific Tumor Immunity.
D. O. Villarreal, M. C. Wise, J. N. Walters, E. L. Reuschel, M. J. Choi, N. Obeng-Adjei, J. Yan, M. P. Morrow, and D. B. Weiner (2014)
Cancer Res. 74, 1789-1800
   Abstract »    Full Text »    PDF »
Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth.
V. Fock, M. Mairhofer, G. R. Otti, U. Hiden, A. Spittler, H. Zeisler, C. Fiala, M. Knofler, and J. Pollheimer (2013)
J. Immunol. 191, 3734-3743
   Abstract »    Full Text »    PDF »
Unconventional protein secretion: an evolving mechanism.
V. Malhotra (2013)
EMBO J. 32, 1660-1664
   Abstract »    Full Text »    PDF »
Interleukin-33 Drives a Proinflammatory Endothelial Activation That Selectively Targets Nonquiescent Cells.
J. Pollheimer, J. Bodin, O. Sundnes, R. J. Edelmann, S. S. Skanland, J. Sponheim, M. J. Brox, E. Sundlisaeter, T. Loos, M. Vatn, et al. (2013)
Arterioscler Thromb Vasc Biol 33, e47-e55
   Abstract »    Full Text »    PDF »
Cardiokines: Recent Progress in Elucidating the Cardiac Secretome.
M. Shimano, N. Ouchi, and K. Walsh (2012)
Circulation 126, e327-e332
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882