title: Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ.
abstract: OBJECTIVE
  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 p110δ subunit of phosphoinositide 3-kinase (PI3K p110δ(D910A/D910A)) revealed defects in B- and 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 p110δ(D910A/D910A) mice were evaluated for colonic inflammation and innate immune dysfunction. Colonic p110δ 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, p110δ(D910A/D910A) mice were backcrossed to IL-10(-/-) mice.
  
  
  RESULTS
  A mild spontaneous colitis was shown in PI3K p110δ(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 p110δ(D910A/D910A) macrophages, augmented toll-like receptor signaling and defective bactericidal activity were observed. Consistent with an important homeostatic role for PI3K p110δ, wild-type mice raised in a germ-free environment markedly up-regulated colonic PI3K p110δ expression with the introduction of the enteric microbiota; however, colitis-prone IL-10(-/-) mice did not. Moreover, PI3K p110δ(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 p110δ in maintaining mucosal homeostasis and could provide insight into the pathogenesis of human inflammatory bowel disease.
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Uno
authors.forename: Kavitha N
authors.initials: KN
authors.lastname: Rao
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.forename: Erin C
authors.initials: EC
authors.lastname: Steinbach
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D007113:Immunity, Innate / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*
chemical_list: D012313:RNA; D058539:Phosphatidylinositol 3-Kinase