ORIGINAL ARTICLE IL-1 Receptor-associated Kinase M Downregulates DSS-induced Colitis Martin Berglund, PhD Student,* Silvia Melgar, PhD, †,‡ Koichi S. Kobayashi, MD, PhD, § Richard A. Flavell, PhD, k Elisabeth Hultgren Ho¨rnquist, PhD, ¶ and Olof H. Hultgren, MD, PhD* ,¶, ** Background: Ulcerative colitis is associated with increased co- lon permeability resulting in bacterial translocation into the lam- ina 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 6 2.1 versus 88.5 6 2.0, *P ¼ 0.002) and an increased macroscopical (2.7 6 0.2 versus 1.6 6 0.1, *P ¼ 0.002) and histopathological (6.0 6 0 versus 3.3 6 0.5, *P ¼ < 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 6 13.5 versus 12.8 6 2.0 pg/mL, *P ¼ 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;16:1778–1786) Key Words: IRAK-M, TLR signaling, colitis, proinflammatory cytokines I nflammatory bowel disease (IBD) is a group of chronic gastrointestinal disorders mainly consisting of Crohn’s disease (CD) and ulcerative colitis (UC). CD is characterized by discontinuous, transmural inflammation affecting the whole gastrointestinal tract, whereas UC leads to continuous inflammation limited to the colonic mucosa and submucosa. The pathogenesis of IBD is not fully known but is thought to involve increased epithelial barrier permeability, inappropri- ate immune responses to the environmental factors such as commensal bacteria, and genetic susceptibility. 1–3 Dextran sulfate sodium (DSS)-induced colitis is a fre- quently used murine model to induce experimental colon inflammation resembling human IBD. 4 Five days of DSS treatment results in severe diarrhea, weight loss, and ulcer- ations of the colonic mucosa in mice on a C57BL/6 back- ground. 5 The mechanisms of DSS-induced colitis are incompletely understood. However, studies have suggested that DSS primarily have cytotoxic effects on epithelial cells disrupting the epithelial barrier, followed by an infiltration of inflammatory cells into the colonic mucosa. 6,7 Indeed, an increased epithelial permeability is seen in first-degree relatives of IBD patients. 8 Interestingly, mice deficient in T and B cells exposed to DSS develop acute intestinal inflammation characterized by an increase in macrophage- derived cytokines. 6,7,9,10 Toll-like receptors (TLRs) are a family of so-called pat- tern recognition receptors (PRRs) recognizing evolutionarily Received for publication February 5, 2010; Accepted February 15, 2010. From the *Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at Go ¨teborg University, Sweden, † Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Ireland, ‡ Immuno-inflammation CEDD GlaxoSmithKline, Stevenage, UK, § Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts, k Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, ¶ Department of Medicine, School of Health and Medical Sciences, Orebro University, Orebro, Sweden, ** Department of Clinical Microbiology, Orebro University Hospital, Orebro, Sweden. Supported by grants from the Go ¨teborg 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 Va ¨stra Go ¨taland (LUA-ALF), the Bengt Ihre’s Foundation, the University of Go ¨teborg, 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. Reprints: Martin Berglund, PhD Student, Department of Microbiology and Immunology, Go ¨teborg University, Box 435, 405 30 Go ¨teborg, Sweden (e-mail: martin.berglund@immuno.gu.se) Copyright V C 2010 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21287 Published online 19 April 2010 in Wiley Online Library (wileyonlinelibrary.com). Inflamm Bowel Dis  Volume 16, Number 10, October 2010 1778