RGD Reference Report - Inhibitor of PI3Kgamma ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells. - Rat Genome Database

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Inhibitor of PI3Kgamma ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells.

Authors: Dutra, RC  Cola, M  Leite, DF  Bento, AF  Claudino, RF  Nascimento, AF  Leal, PC  Calixto, JB 
Citation: Dutra RC, etal., Br J Pharmacol. 2011 May;163(2):358-74. doi: 10.1111/j.1476-5381.2011.01226.x.
RGD ID: 6482682
Pubmed: PMID:21244371   (View Abstract at PubMed)
PMCID: PMC3087137   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1476-5381.2011.01226.x   (Journal Full-text)

BACKGROUND AND PURPOSE: Phosphoinositide 3-kinase-gamma (PI3Kgamma) 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 PI3Kgamma 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-1beta, CXCL-1/KC, MIP-2 and TNF-alpha 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-kappa (NF-kappaB) inhibition. Importantly, the PI3Kgamma 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-kappaB 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
colitis  ISOPik3cg (Mus musculus)6482682; 6482682 RGD 
colitis  IMP 6482682 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pik3cg  (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma)

Genes (Mus musculus)
Pik3cg  (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma)

Genes (Homo sapiens)
PIK3CG  (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma)


Additional Information