PMID- 21244371
OWN - NLM
STAT- MEDLINE
DCOM- 20111101
LR  - 20211020
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 163
IP  - 2
DP  - 2011 May
TI  - Inhibitor of PI3Kgamma ameliorates TNBS-induced colitis in mice by affecting the 
      functional activity of CD4+CD25+FoxP3+ regulatory T cells.
PG  - 358-74
LID - 10.1111/j.1476-5381.2011.01226.x [doi]
AB  - 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.
CI  - (c) 2011 The Authors. British Journal of Pharmacology (c) 2011 The British 
      Pharmacological Society.
FAU - Dutra, R C
AU  - Dutra RC
AD  - Department of Pharmacology, Center of Biological Sciences, Universidade Federal 
      de Santa Catarina, Florianopolis, SC, Brazil.
FAU - Cola, M
AU  - Cola M
FAU - Leite, D F P
AU  - Leite DF
FAU - Bento, A F
AU  - Bento AF
FAU - Claudino, R F
AU  - Claudino RF
FAU - Nascimento, A F Z
AU  - Nascimento AF
FAU - Leal, P C
AU  - Leal PC
FAU - Calixto, J B
AU  - Calixto JB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione)
RN  - 0 (CD4 Antigens)
RN  - 0 (Cytokines)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, rat)
RN  - 0 (Interleukin-2 Receptor alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinoxalines)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 8T3HQG2ZC4 (Trinitrobenzenesulfonic Acid)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - CD4 Antigens/*metabolism
MH  - Cells, Cultured
MH  - Colitis/chemically induced/*drug therapy/immunology
MH  - Colon/drug effects/immunology/pathology
MH  - Cytokines/metabolism
MH  - Forkhead Transcription Factors/*metabolism
MH  - Interleukin-2 Receptor alpha Subunit/*metabolism
MH  - Intestinal Mucosa/drug effects/immunology/pathology
MH  - Male
MH  - Matrix Metalloproteinase 9/biosynthesis
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - Neutrophil Infiltration
MH  - Neutrophils/drug effects/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Quinoxalines/pharmacology/*therapeutic use
MH  - T-Lymphocytes, Regulatory/*metabolism
MH  - Thiazolidinediones/pharmacology/*therapeutic use
MH  - *Trinitrobenzenesulfonic Acid
MH  - Vascular Endothelial Growth Factor A/biosynthesis
PMC - PMC3087137
EDAT- 2011/01/20 06:00
MHDA- 2011/11/02 06:00
PMCR- 2012/05/01
CRDT- 2011/01/20 06:00
PHST- 2011/01/20 06:00 [entrez]
PHST- 2011/01/20 06:00 [pubmed]
PHST- 2011/11/02 06:00 [medline]
PHST- 2012/05/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.2011.01226.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2011 May;163(2):358-74. doi: 10.1111/j.1476-5381.2011.01226.x.