The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease.
The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease.
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DOI：
10.1186/1471-230x-10-60
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发表时间：
2010-06-10
影响因子：
2.4
通讯作者：
Bassaganya-Riera J
中科院分区：
文献类型：
--
作者：
Guri AJ;Mohapatra SK;Horne WT 2nd;Hontecillas R;Bassaganya-Riera J
过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor γ，PPAR γ）是一种核受体，其活化已被证明可调节巨噬细胞和T细胞介导的炎症。本研究的目的是探讨T细胞中PPAR γ的缺失调节免疫细胞分布和结肠基因表达以及实验性IBD严重程度的机制。用含2.5%葡聚糖硫酸钠的饮用水对PPAR γ flfl; CD 4 Cre+（CD 4cre）或Cre-（WT）小鼠进行攻击，持续0、2或7天。在临床和组织病理学上对小鼠的疾病严重程度进行评分。使用流式细胞术评估血液、脾脏和肠系膜淋巴结（MLN）中的淋巴细胞和巨噬细胞群。使用Affytron微阵列分析结肠粘膜中的整体基因表达。T细胞中PPAR γ的缺乏加速了疾病的发生和体重减轻。结肠组织病理学检查显示，在第7天，CD 4cre小鼠的上皮糜烂、白细胞浸润和粘膜增厚显著增加。CD 4cre小鼠在血液和MLN中分别具有比WT小鼠更多的CD 8 + T细胞和更少的CD 4 + FoxP 3+调节性T细胞（Treg）和IL 10 + CD 4 + T细胞。转录组学分析显示，在CD 4cre小鼠中，由于DSS攻击，约3000个基因被转录改变。这些包括第7天粘附分子、促炎细胞因子白细胞介素-6（IL-6）和IL-1β以及细胞因子信号转导抑制因子3（SOCS-3）的mRNA表达上调。基因集富集分析（GSEA）显示，T细胞中PPAR γ缺失的小鼠结肠中，核糖体和Krebs循环途径下调，而凋亡途径上调。T细胞中的PPAR γ表达通过在疾病后期调节粘附分子和炎症介质的结肠表达，同时促进Treg募集到粘膜诱导位点，参与预防肠道炎症。
Peroxisome proliferator-activated receptor γ (PPAR γ) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. PPAR γ flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. The deficiency of PPAR γ in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+FoxP3+ regulatory T cells (Treg) and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR γ in T cells. The expression of PPAR γ in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive sites.