Altered Macrophage Function Contributes to Colitis in Mice Defective in the Phosphoinositide-3 Kinase Subunit p110δ

被引:75
作者
Uno, Jennifer K. [1 ,2 ]
Rao, Kavitha N. [3 ]
Matsuoka, Katsuyoshi [1 ]
Sheikh, Shehzad Z. [1 ,2 ]
Kobayashi, Taku [1 ]
Li, Fengling [1 ,2 ]
Steinbach, Erin C. [1 ,2 ]
Sepulveda, Antonia R. [4 ]
Vanhaesebroeck, Bart [5 ]
Sartor, R. Balfour [1 ,2 ]
Plevy, Scott E. [1 ,2 ]
机构
[1] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA
[2] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[3] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA
[4] Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA
[5] Queen Mary Univ London, Inst Canc, Ctr Cell Signalling, London, England
基金
美国国家卫生研究院;
关键词
Inflammatory Bowel Diseases; Innate Immunity; PI3-Kinase; Enteric Microbiota; KAPPA-B ACTIVATION; 3-KINASE P110-DELTA; NEGATIVE REGULATION; IL-12; PRODUCTION; DISTINCT ROLES; CUTTING EDGE; NITRIC-OXIDE; BACTERIA; DISEASE; CELL;
D O I
10.1053/j.gastro.2010.07.008
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: Innate immune responses are crucial for host defense against pathogens but need to be tightly regulated to prevent chronic inflammation. Initial characterization of mice with a targeted inactivating mutation in the p110 delta subunit of phosphoinositide 3-kinase (PI3K p110 delta(D910A/D910A)) revealed defects in Band T-cell signaling and chronic colitis. Here, we further characterize features of inflammatory bowel diseases in these mice and investigate underlying innate immune defects. METHODS: Colons and macrophages from PI3K p110 delta(D910A/D910A) mice were evaluated for colonic inflammation and innate immune dysfunction. Colonic p110 delta messenger RNA expression was examined in interleukin (IL)-10(-/-) and wild-type germ-free mice during transition to a conventional microbiota. To assess polygenic impact on development of colitis, p110 delta(D910A/D910A) mice were back-crossed to IL-10(-/-) mice. RESULTS: A mild spontaneous colitis was shown in PI3K p110 delta(D910A/D910A) mice at 8 weeks, with inflammation increasing with age. An inflammatory mucosal and systemic cytokine profile was characterized by expression of IL-12/23. In PI3K p110 delta(D910A/D910A) macrophages, augmented toll-like receptor signaling and defective bactericidal activity were observed. Consistent with an important homeostatic role for PI3K p110 delta, wild-type mice raised in a germ-free environment markedly up-regulated colonic PI3K p110 delta expression with the introduction of the enteric microbiota; however, colitis-prone IL-10(-/-) mice did not. Moreover, PI3K p110 delta(D910A/D910A) mice crossed to IL-10(-/-) mice developed severe colitis at an early age. CONCLUSIONS: This study describes a novel model of experimental colitis that highlights the importance of PI3K p110 delta in maintaining mucosal homeostasis and could provide insight into the pathogenesis of human inflammatory bowel disease.
引用
收藏
页码:1642 / +
页数:18
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