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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.

Abstract：

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.

journal_name

Inflamm Bowel Dis

journal_title

Inflammatory bowel diseases

authors

Prescott D,Atkinson B,Döring A,Brown S,Petri B,McKay DM,Waterhouse CC

doi

10.1097/MIB.0b013e31827feb84

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

489-500

issue

eissn

1078-0998

issn

1536-4844

journal_volume

pub_type

杂志文章

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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.