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IL-1 receptor-associated kinase M downregulates DSS-induced colitis†

Berglund, Martin PhD Student1,*; Melgar, Silvia PhD2,3; Kobayashi, Koichi S. MD, PhD4; Flavell, Richard A. PhD6; Hörnquist, Elisabeth Hultgren PhD5; Hultgren, Olof H. MD, PhD1,5,7

doi: 10.1002/ibd.21287
Original Basic Science Articles: IRAK-M and DSS-induced Colitis: Original Basic Science Articles

Background: Ulcerative colitis is associated with increased colon permeability resulting in bacterial translocation into the lamina propria. We investigate the importance of the Toll-like receptor (TLR) regulating protein IL-1 receptor-associated kinase M (IRAK-M) using the erosive dextran sulfate sodium (DSS)-induced model of colitis.

Methods: IRAK-M-competent and -incompetent mice were treated with 3% DSS for 5 days followed by 2 days of regular drinking water. Clinical signs of disease were followed for 7 days. At day 7 the mice were sacrificed and plasma and tissue were collected for histopathological examination and analyses of the production of cytokines and chemokines as well as expression of T-cell transcription factors.

Results: At day 7 IRAK-M-deficient mice display a reduced total body weight (77.1 ± 2.1 versus 88.5 ± 2.0, *P = 0.002) and an increased macroscopical (2.7 ± 0.2 versus 1.6 ± 0.1, *P = 0.002) and histopathological (6.0 ± 0 versus 3.3 ± 0.5, *P = < 0.001) colon score compared to wildtype mice. Furthermore, IRAK-M-deficient mice have increased colon mRNA expression of proinflammatory cytokines and increased tumor necrosis factor concentrations (41.1 ± 13.5 versus 12.8 ± 2.0 pg/mL, *P = 0.010) in plasma.

Conclusions: This is the first report examining the role of IRAK-M in colitis. We find that IRAK-M is of critical importance in downregulating induction and progression of DSS colitis, and thereby suggesting that IRAK-M might be a target for future interventional therapies. (Inflamm Bowel Dis 2010)

1Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, Sweden

2Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Ireland

3Immuno-inflammation CEDD GlaxoSmithKline, Stevenage, UK

4Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts

5Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

6Department of Medicine, School of Health and Medical Sciences, Orebro University, Orebro, Sweden

7Department of Clinical Microbiology, Orebro University Hospital, Orebro, Sweden

*Reprints: Department of Microbiology and Immunology, Göteborg University, Box 435, 405 30 Göteborg, Sweden

Email: martin.berglund@immuno.gu.se

Received for publication 5 February 2010; Accepted 15 February 2010.

Published online 19 April 2010 in Wiley Online Library (wileyonlinelibrary.com).

Supported by grants from the Göteborg Medical Society, the Swedish Medical Society, the Olle Engkvist Foundation, the Karl and Annie Leon Foundation, the Swedish Research Council-Medicine and Health, the Swedish Cancer Society, the Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (LUA-ALF), the Bengt Ihre's Foundation, the University of Göteborg, and the Mucosal Immunology and Vaccine Center (MIVAC). The Alimentary Pharmabiotic Centre is supported, in part, by Science Foundation Ireland and GlaxoSmithKline. R.A. Flavell is an investigator of the Howard Hughes Medical Institute.

© Crohn's & Colitis Foundation of America, Inc.
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