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

Abstract

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.

• Authors: Martin Berglund, Silvia Melgar, Koichi S Kobayashi, Richard A Flavell, Elisabeth Hultgren Hörnquist, Olof H Hultgren
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 16 Issue 10 Pg. 1778-86 (Oct 2010) ISSN: 1536-4844 [Electronic] England
• PMID: 20848470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• RNA, Messenger
• Dextran Sulfate
• Interleukin-1 Receptor-Associated Kinases
• Irak3 protein, mouse

Topics

• Animals
• Colitis (chemically induced, pathology, prevention & control)
• Cytokines (genetics, metabolism)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Down-Regulation
• Female
• Interleukin-1 Receptor-Associated Kinases (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction