Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis
Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis
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DOI：
10.1097/00054725-200209000-00004
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发表时间：
2002-09-01
影响因子：
4.9
通讯作者：
Blumberg, RS
中科院分区：
文献类型：
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作者：
Saubermann, LJ;Nakajima, A;Blumberg, RS
过氧化物酶体增殖体激活受体（PPARgamma）是核转录因子家族的一员，先前已被证明具有抗炎活性。PPARgamma激活在免疫反应发展中的作用还不太清楚。通过评估PPARgamma杂合子小鼠（PPARgamma(+/-)）和特异性PPARgamma激动剂配体结合，我们评估了PPARgamma激活在一个描述良好的结肠炎模型中的免疫作用。与野生型小鼠相比，PPARgamma（+/-）小鼠对右旋糖酐硫酸钠（DSS）诱导的结肠炎的易感性增加（以体重、组织学损伤和生存率来定义）。三种不同的PPARgamma配体（曲格列酮、吡格列酮和罗格列酮）在结肠炎发病前施用时显示出有益的剂量相关治疗效果。然而，当结肠炎发作后发生PPARgamma配体激活时，没有观察到保护作用。定量逆转录-聚合酶链反应显示，PPARgamma配体治疗引起的dss诱导炎症的减少与干扰素γ和肿瘤坏死因子α的降低以及白细胞介素(IL)-4和IL-10水平的升高有关。与这种向辅助性T细胞因子（Th2）主导的转变相一致，PPARgamma配体处理刺激了GATA-3表达的增加。这些结果表明，PPARgamma配体在肠道炎症中的保护作用可能是由于免疫偏离Th1而转向Th2细胞因子的产生。
Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of a nuclear transcription factor family, has been previously demonstrated to have anti inflammatory activity. The effects of PPARgamma activation in the development of an immune response are less well characterized. Through evaluation of PPARgamma heterozygote mice (PPARgamma(+/-)) and specific PPARgamma agonist ligand binding, we evaluated the immunologic effects of PPARgamma activation in a well-described model of colitis. Increased susceptibility to dextran sodium sulfate (DSS)-induced colitis as defined by body weights, histologic injury, and survival was observed in the PPARgamma(+/-) mice in comparison to wild-type mice. Three different PPARgamma ligands (troglitazone, pioglitazone, and rosiglitazone) demonstrated beneficial dose-related treatment effects when administered prior to the onset of colitis. However, no protection was observed when PPARgamma ligand activation occurred after the onset of colitis. The reduction in DSS-induced inflammation noted with PPARgamma ligand treatment was associated with decreased interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4 and IL-10 levels as assessed by quantitative reverse transcriptase-polymerase chain reaction. Consistent with this shift towards a T helper (Th2) cytokine dominance, PPARgamma ligand treatment stimulated increased GATA-3 expression. These results indicate that the protective effects exhibited by PPARgamma ligands in intestinal inflammation may be due to immune deviation away from Th1 and towards Th2 cytokine production.