Inflammatory Bowel Diseases

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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e31827feb84
Original Basic Science Articles

Loss of Phosphoinositide 3-Kinase p110γ is Protective in the Acute Phase but Detrimental in the Resolution Phase of Hapten-Induced Colitis

Prescott, David BSc*,†,‡; Atkinson, Bronwyn BSc*,‡,§; Döring, Axinia PhD*,‡,§; Brown, Shannon BSc*,‡,§,‖; Petri, Björn PhD, MSc; McKay, Derek M. PhD*,†,‡; Waterhouse, Christopher C. M. MD, PhD, FRCPC*,‡,§,‖

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Background: Pharmacologic inhibition or genetic ablation of phosphoinositide 3-kinase gamma (PI3Kγ) has been shown to be protective against experimental colitis. However, the role of PI3Kγ in the resolution phase of colitis remains unexplored. In this study, we assess the effects of genetic knockout of PI3Kγ on the induction and resolution of colitis induced by the hapten trinitrobenzene sulfonic acid (TNBS).

Methods: Colitis was induced in wild-type C57/Bl6 or PI3Kγ−/− mice by intrarectal administration of 2.5 mg of TNBS in 50% ethanol. Body weights were monitored daily, and colon tissues were collected at days 3, 7, or 14 after treatment, and colitis was assessed using disease activity and histologic damage scores, measurement of tissue myeloperoxidase and neutrophil infiltration, and local cytokine production.

Results: Mice lacking PI3Kγ were significantly protected from disease during the acute phase (day 3) of TNBS colitis. However, PI3Kγ−/− mice have difficulty resolving acute inflammation because they failed to restore lost weight and had significantly elevated histologic damage scores and tissue myeloperoxidase levels at days 7 and 14 after TNBS administration compared with wild-type controls. This phenomenon was dependent on presensitization with TNBS and seems to involve an inability to clear invading bacteria, resulting in the generation of a persistent inflammatory cytokine response.

Conclusions: This study confirms that PI3Kγ plays a role in the induction of colitis. However, PI3Kγ is also required for the resolution of intestinal damage following acute inflammation. This must be taken into consideration before the inhibition of PI3Kγ can be used as a treatment for disorders such as inflammatory bowel disease.

© Crohn's & Colitis Foundation of America, Inc.

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