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International Immunology Advance Access originally published online on March 28, 2008
International Immunology 2008 20(6):739-752; doi:10.1093/intimm/dxn032
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD

Alejandro V. Villarino1,4, David Artis1, Jelena S. Bezbradica2,5, Omer Miller4, Christiaan J. M. Saris3, Sebastian Joyce2 and Christopher A. Hunter1

1 Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
2 Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
3 Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA 91320, USA
4 Present address: Department of Pathology, University of California, San Francisco, School of Medicine, 513 Parnassus Avenue, San Francisco, CA 94143, USA
5 Present address: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA

Correspondence to: A. V. Villarino; E-mail: alejandro.villarino{at}ucsf.edu

Members of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis in mice. We report that, compared with IL-10-deficient animals, which succumb to chronic intestinal disease at 3-6 months of age, mice lacking both IL-10 and the IL-27R (IL-27R/WSX-1) exhibit delayed pathology and prolonged survival (>1 year). Moreover, unlike highly susceptible IL-10-deficient counterparts, they were able to clear infection with Trichuris muris, a colon-dwelling nematode. In both models of intestinal inflammation, improved clinical outcome was associated with reduced inflammation and profound attenuation of Th1 responses and, consistent with these in vivo findings, we confirmed that during in vitro differentiation, IL-27 directly promotes CD4+ T cell IFN-{gamma} production through effects on Tbet, a key Th1 transcription factor. We also found that its ability to suppress Th2 responses, which was clearly evident in helminth-infected IL-10–/–IL-27R–/– mice, was largely Tbet independent. Taken together, these studies demonstrate that, in the absence of IL-10, IL-27 can promote Th1-type and suppress Th2-type intestinal inflammation but, ultimately, is not required for the development of inflammatory bowel disease.

Keywords: colitis, helminth infection, IFN-{gamma}, IL-10, IL-27

Transmitting editor: G. Trinchieri

Received 10 October 2007, accepted 28 February 2008.


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