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T cell PPAR? is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD.

ABSTRACT: The phytohormone abscisic acid (ABA) has been shown to be effective in ameliorating chronic and acute inflammation. The objective of this study was to investigate whether ABA's anti-inflammatory efficacy in the gut is dependent on peroxisome proliferator-activated receptor ? (PPAR?) in T cells. PPAR?-expressing and T cell-specific PPAR? null mice were fed diets with or without ABA (100 mg/kg) for 35 days prior to challenge with 2.5% dextran sodium sulfate. The severity of clinical disease was assessed daily, and mice were euthanized on Day 7 of the dextran sodium sulfate challenge. Colonic inflammation was assessed through macroscopic and histopathological examination of inflammatory lesions and real-time quantitative RT-PCR-based quantification of inflammatory genes. Flow cytometry was used to phenotypically characterize leukocyte populations in the blood and mesenteric lymph nodes. Colonic sections were stained immunohistochemically to determine the effect of ABA on colonic regulatory T (T(reg)) cells. ABA's beneficial effects on disease activity were completely abrogated in T cell-specific PPAR? null mice. Additionally, ABA improved colon histopathology, reduced blood F4/80(+)CD11b(+) monocytes, increased the percentage of CD4(+) T cells expressing the inhibitory molecule cytotoxic T lymphocyte antigen 4 in blood and enhanced the number of T(reg) cells in the mesenteric lymph nodes and colons of PPAR?-expressing but not T cell-specific PPAR? null mice. We conclude that dietary ABA ameliorates experimental inflammatory bowel disease by enhancing T(reg) cell accumulation in the colonic lamina propria through a PPAR?-dependent mechanism.

SUBMITTER: Guri AJ

PROVIDER: S-EPMC3117068 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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T cell PPARγ is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD.

Guri Amir J AJ Evans Nicholas P NP Hontecillas Raquel R Bassaganya-Riera Josep J

The Journal of nutritional biochemistry 20101215 9

The phytohormone abscisic acid (ABA) has been shown to be effective in ameliorating chronic and acute inflammation. The objective of this study was to investigate whether ABA's anti-inflammatory efficacy in the gut is dependent on peroxisome proliferator-activated receptor γ (PPARγ) in T cells. PPARγ-expressing and T cell-specific PPARγ null mice were fed diets with or without ABA (100 mg/kg) for 35 days prior to challenge with 2.5% dextran sodium sulfate. The severity of clinical disease was as ...[more]

PMID: 21109419

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Project description:Besides their long-known critical role in embryonic growth and in cancer development and progression, erythropoietin-producing hepatocellular carcinoma type B (EphB) receptor tyrosine kinases and their ephrin-B ligands are involved in the modulation of immune responses and in remodeling and maintaining the integrity of the intestinal epithelial layer. These processes are critically involved in the pathogenesis of inflammatory-based disorders of the gut, like inflammatory bowel diseases (IBDs). Accordingly, our aim was to investigate the role of the EphB/ephrin-B system in intestinal inflammation by assessing the local and systemic effects produced by its pharmacological manipulation in 2,4,6-trinitrobenzenesulfonic acid (TNBS)- (Th1-dependent model) and dextran sulphate sodium (DSS)- (innate response model) induced colitis in mice. To this purpose, we administered chimeric Fc-conjugated proteins, allegedly able to uni-directionally activate either forward (ephrin-B1-Fc) or reverse (EphB1-Fc) signaling, and the soluble monomeric EphB4 extracellular domain protein, that, simultaneously interfering with both signaling pathways, acts as EphB/ephrin-B antagonist.The blockade of the EphB/ephrin-B forward signaling by EphB4 and EphB1-Fc was ineffective against DSS-induced colitis while it evoked remarkable beneficial effects against TNBS colitis: it counteracted all the evaluated inflammatory responses and the changes elicited on splenic T lymphocytes subpopulations, without preventing the appearance of a splice variant of ephrin-B2 gene elicited by the haptenating agent in the colon. Interestingly, EphB4, preferentially displacing EphB4/ephrin-B2 interaction over EphB1/ephrin-B1 binding, was able to promote Tumor Necrosis Factor alpha (TNFα) release by splenic mononuclear cells in vitro. On the whole, the collected results point to a potential role of the EphB/ephrin-B system as a pharmacological target in intestinal inflammatory disorders and suggest that the therapeutic efficacy of its blockade seemingly works through the modulation of immune responses, independent of the changes at the transcriptional and translational level of EphB4 and ephrin-B2 genes.

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T cell PPAR? is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD.

Publications

T cell PPARγ is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD.

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