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PNAS 108 (40): 16711-16716

Copyright © 2011 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / IMMUNOLOGY

Interleukin 37 expression protects mice from colitis

Eóin N. McNameea,b,c, Joanne C. Mastersona,d, Paul Jedlickac,e, Martine McManusc,e, Almut Grenza,b,c, Colm B. Collinsa,d, Marcel F. Noldf, Claudia Nold-Petryf, Philip Buflerg, Charles A. Dinarellof,1, and Jesús Rivera-Nievesh,1

aMucosal Inflammation Program, Department of Medicine, dSection of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Gastrointestinal Eosinophilic Disease Program, Children's Hospital Colorado, Departments of ePathology and bAnesthesiology, and fDivision of Infectious Diseases, c University of Colorado Denver, Aurora, CO 80045; gChildren's Hospital, Ludwig-Maximilians University, D-80337 Munich, Germany; and hInflammatory Bowel Disease Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA 92093

Contributed by Charles A. Dinarello, August 3, 2011 (sent for review March 13, 2011)

Abstract: IL-37, a newly described member of the IL-1 family, functions as a fundamental inhibitor of innate inflammation and immunity. In the present study, we examined a role for IL-37 during experimental colitis. A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to dextran sulfate sodium (DSS)-induced colitis. Despite the presence of a CMV promoter to drive expression of IL-37, mRNA transcripts were not present in colons at the resting state. Expression was observed only upon disruption of the epithelial barrier, with a six- to sevenfold increase (P = 0.02) on days 3 and 5 after continuous exposure to DSS. During the development of colitis, clinical disease scores were reduced by 50% (P < 0.001), and histological indices of colitis were one-third less in hIL-37tg mice compared with WT counterparts (P < 0.001). Reduced inflammation was associated with decreased leukocyte recruitment into the colonic lamina propria. In addition, release of IL-1β and TNFα from ex vivo colonic explant tissue was decreased 5- and 13-fold, respectively, compared with WT (P ≤ 0.005), whereas IL-10 was increased sixfold (P < 0.001). However, IL-10 was not required for the anti-inflammatory effects of IL-37 because IL-10-receptor antibody blockade did not reverse IL-37-mediated protection. Mechanistically, IL-37 originating from hematopoietic cells was sufficient to exert anti-inflammatory effects because WT mice reconstituted with hIL-37tg bone marrow were protected from colitis. Thus, IL-37 emerges as key modulator of intestinal inflammation.

Key Words: cytokine • intestine • inflammatory bowel disease


Author contributions: E.N.M., C.A.D., and J.R.-N. designed research; E.N.M., J.C.M., M.M., A.G., C.B.C., and C.A.D. performed research; M.F.N., C.N.-P., P.B., and C.A.D. contributed new reagents/analytic tools; E.N.M., J.C.M., P.J., M.M., C.A.D., and J.R.-N. analyzed data; E.N.M., C.A.D., and J.R.-N. wrote the paper.

The authors declare no conflict of interest.

See Commentary on page 16493.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1111982108/-/DCSupplemental.

1To whom correspondence may be addressed. E-mail: cdinarello{at}mac.com or jriveran{at}ucsd.edu.


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