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Functional deficits in IL ‐10 and Phosphatidyl Inositol‐3 Kinase (PI3K) contribute to the development of severe colitis.
Author(s) -
Uno Jennifer K,
Matsuoka Katsuyoshi,
Sheikh Shehzad Z,
Elloumi Houda,
Li Fengling,
Plevy Scott E.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1007.7
Subject(s) - colitis , p110α , pi3k/akt/mtor pathway , mutant , pathogenesis , inflammatory bowel disease , medicine , phenotype , immunology , biology , disease , gene , genetics , signal transduction
Human IBD is a polygenic disorder with genetic modifiers influencing the severity of disease. The IL‐10 −/− mouse is an established model for IBD. We previously described mice harboring a mutation in the p110δ subunit of PI3K develop chronic colitis. The phenotype of colitis is mild in IL‐10 −/− and PI3K p110δ mutant mice on a C57BL/6 background. Moreover, we describe partial but not complete abrogation of colonic PI3K p110δ expression in germ free IL‐10 −/− mice transitioned to SPF housing. Here, we investigate whether a combined genetic defect alters the phenotype of colitis. IL‐10 −/− mice were crossed with PI3K p110δ mutant miceto create IL‐10 −/− /PI3K p110δ mutant mice. While, 4‐week‐old PI3K p110δ mutant and IL‐10 −/− mice display little to no inflammation, IL‐10 −/− /PI3K p110δ mutant mice develop severe colitis. 100% of mice developed colitis by 4 months of age, over 50% displayed severe inflammatory changes by 6 weeks and 40% of the mice developed rectal prolapse. Colitis scores from IL‐10 −/− /PI3K p110δ mutant mice were significantly higher than age matched PI3K p110δ mutant and IL‐10 −/− mice. Colonic explant cultures demonstrated increased levels of IL‐12 p40, p70 and IL‐23 from double deficient mice compared to IL‐10 −/− and PI3K p110δ mutant mice (n = 8, p= 0.05). This work highlights the importance of genetic modifiers on disease outcome in IBD and may provide valuable insight into the pathogenesis of human IBD.