IL-1 Receptor-associated Kinase M Downregulates DSS-induced Colitis

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 +/- 60.5, *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; 16: 1778-1786)