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Altered innate immunity contributes to the development of colitis in PI3K p110d mutant mice
Author(s) -
Uno Jennifer Kikue,
Rao Kavitha,
Matsuoka Katsuyoshi,
Li Fengling,
Sartor R. Balfour,
Plevy Scott E
Publication year - 2008
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.22.1_supplement.852.1
Subject(s) - innate immune system , pi3k/akt/mtor pathway , biology , immune system , immunology , immunity , colitis , microbiology and biotechnology , acquired immune system , signal transduction
The phosphoinositide‐3 kinase (PI3K) pathway is an important negative regulator of innate immune signaling. Initial characterization of mice with a targeted mutation in the p110δ subunit of PI3K revealed chronic, focal colitis. However, immunomodulatory effects of PI3K p110δ in innate immunity remain unclear. We demonstrate that PI3K p110δ mutant macrophages (splenic, bone marrow derived & intestinal) are hyperresponsive to TLR signaling, producing increased levels of IL‐12 p40, IL‐12 p70, and IL‐23. Likewise, increased colonic IL‐12/23, IFN‐γ, and IL‐17 are detected, indicating that aberrant regulation of innate immune signaling could contribute to the development of Th1/Th17 mediated colitis. An innate mucosal inflammatory response is essential for clearance of enteric microorganisms that breach the epithelial barrier. However, excessive and prolonged activation of these inflammatory pathways is detrimental to the host and may contribute to the pathogenesis of IBD. We therefore sought to determine the role of PI3K p110δ signaling in killing of intracellular enteric bacteria by macrophages. P13K p110δ mutant macrophages display significantly decreased killing of intracellular K12 E. coli compared to wild type macrophages. In addition, decreased bacterial killing was associated with marked increases in IL‐12 p40 production in p110δ mutant macrophages as compared to wild type macrophages (mutant vs. wild type, p= 0.05, n=3). In conclusion, PI3K p110δ plays an important role in dampening innate immune responses necessary for maintaining gut homeostasis.