التفاصيل البيبلوغرافية
| العنوان: |
Inhibitor of PI3Kγ ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells. |
| المؤلفون: |
Dutra, RC, Cola, M, Leite, DFP, Bento, AF, Claudino, RF, Nascimento, AFZ, Leal, PC, Calixto, JB, Dutra, R C, Leite, D F P, Bento, A F, Claudino, R F, Nascimento, A F Z, Leal, P C, Calixto, J B |
| المصدر: |
British Journal of Pharmacology; May2011, Vol. 163 Issue 2, p358-374, 17p, 8 Graphs |
| مصطلحات موضوعية: |
ENZYME inhibitors, PHOSPHOINOSITIDES, LIPOPOLYSACCHARIDES, POLYMERASE chain reaction, COLITIS, T cells, LABORATORY mice, INFLAMMATORY bowel disease treatment |
| مستخلص: |
Background and Purpose: 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.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-1β, CXCL-1/KC, MIP-2 and TNF-α 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-κ (NF-κB) inhibition. Importantly, the PI3Kγ 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-κB 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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