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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*,‡,§,‖

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

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.

Article first published online 26 December 2012

*Gastrointestinal Research Group

Department of Physiology & Pharmacology

Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases

§Department of Paediatrics; Faculty of Medicine, University of Calgary

Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada.

Reprints: Christopher C. M. Waterhouse, MD, PhD, FRCPC, Division of Paediatric Gastroenterology, Department Physiology & Pharmacology, Alberta Children's Hospital University of Calgary, 2888 Shaganappi Trail NW 3330 Hospital Drive NW, Calgary, Alberta T3B 6A8, Canada (e-mail: chris.waterhouse@albertahealthservices.ca).

The study was supported by the Alberta Children's Hospital Foundation (C.C.M.W.), and an operating grant from the Canadian Institutes of Health Research (CIHR: MOP-171492 to D.M.M). D. Prescott is a recipient of doctoral studentship awards from the National Sciences and Engineering Research Council of Canada and the Alberta-Innovates Health Solutions (formerly the Alberta Heritage Foundation for Medical Research). D. M. McKay is an Alberta Heritage Foundation for Medical Research Scientist and recipient of a Canada Research Chair (Tier 1) in Intestinal Immunophysiology.

The authors have no conflicts of interest to disclose.

Received May 17, 2012

Accepted June 06, 2012

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