Dataset Information

Inhibitor of PI3K? ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells.

ABSTRACT:

Background and purpose

Phosphoinositide 3-kinase-? (PI3K?) is implicated in many pathophysiological conditions, and recent evidence has suggested its involvement in colitis. In the present study, we investigated the effects of AS605240, a relatively selective PI3K? inhibitor, in experimental colitis and its underlying mechanisms.

Experimental approach

Acute colitis was induced in mice by treatment with trinitrobenzene sulphonic acid (TNBS), and the effect of AS605240 on colonic injury was assessed. Pro-inflammatory mediators and cytokines were measured by immunohistochemistry, elisa, real time-polymerase chain reaction and flow cytometry.

Key results

Oral administration of AS605240 significantly attenuated TNBS-induced acute colitis and diminished the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. The colonic levels and expression of IL-1?, CXCL-1/KC, MIP-2 and TNF-? were also reduced following therapeutic treatment with AS605240. Moreover, AS605240 reduced MIP-2 levels in a culture of neutrophils stimulated with lipopolysaccharide. The mechanisms underlying these actions of AS605240 are related to nuclear factor-? (NF-?B) inhibition. Importantly, the PI3K? inhibitor also up-regulated IL-10, CD25 and FoxP3 expression. In addition, a significant increase in CD25 and FoxP3 expression was found in isolated lamina propria CD4+ T cells of AS605240-treated mice. The effect of AS605240 on Treg induction was further confirmed by showing that concomitant in vivo blockade of IL-10R significantly attenuated its therapeutic activity.

Conclusions and implications

These results suggest that AS605240 protects mice against TNBS-induced colitis by inhibiting multiple inflammatory components through the NF-?B pathway while simultaneously inducing an increase in the functional activity of CD4+CD25+ Treg. Thus, AS605240 may offer a promising new therapeutic strategy for the treatment of inflammatory bowel diseases.

SUBMITTER: Dutra RC

PROVIDER: S-EPMC3087137 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Inhibitor of PI3Kγ ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells.

Dutra R C RC Cola M M Leite D F P DF Bento A F AF Claudino R F RF Nascimento A F Z AF Leal P C PC Calixto J B JB

British journal of pharmacology 20110501 2

<h4>Background and purpose</h4>Phosphoinositide 3-kinase-γ (PI3Kγ) is implicated in many pathophysiological conditions, and recent evidence has suggested its involvement in colitis. In the present study, we investigated the effects of AS605240, a relatively selective PI3Kγ inhibitor, in experimental colitis and its underlying mechanisms.<h4>Experimental approach</h4>Acute colitis was induced in mice by treatment with trinitrobenzene sulphonic acid (TNBS), and the effect of AS605240 on colonic in ...[more]

PMID: 21244371

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