PPARβ/δ protects against experimental colitis through a ligand-independent mechanism
PPARβ/δ protects against experimental colitis through a ligand-independent mechanism
复制标题
DOI：
10.1007/s10620-006-9644-9
复制
发表时间：
2007-11-01
影响因子：
3.1
通讯作者：
Peters, Jeffrey M.
中科院分区：
文献类型：
--
作者：
Hollingshead, Holly E.;Morimura, Keiichirou;Peters, Jeffrey M.
过氧化物酶体增殖物激活受体（PPARs）β/δ和γ在炎症反应基因的负调控中具有重叠作用。配体激活的过氧化物酶体增殖物激活受体γ保护小鼠免受实验性结肠炎。PPARbeta/delta可以负调节炎症，并且在结肠上皮细胞中高度表达，因此PPARbeta/delta也可能在实验性结肠炎中发挥作用。在这些研究中，结肠炎是由葡聚糖硫酸钠（DSS）治疗在野生型和PPAR β/δ-null小鼠，有和没有PPAR β/δ特异性配体GW 0742诱导。与类似处理的野生型小鼠相比，PPAR β/δ缺失小鼠表现出对DSS诱导的结肠炎的敏感性增加，如体重减轻、结肠长度、结肠形态、髓过氧化物酶活性和编码炎性标志物干扰素γ、肿瘤坏死因子-α和白细胞介素-6的mRNA表达增加的显著差异所示。有趣的是，这些差异不受任何基因型中的PPAR β/δ的配体活化的影响。这些研究表明，结肠上皮中的PPAR β/δ表达通过配体非依赖性机制抑制炎症并防止DSS诱导的结肠炎。
Peroxisome proliferator-activated receptors (PPARs) beta/delta and gamma have overlapping roles in the negative regulation of inflammatory response genes. Ligand activation of PPAR gamma protects against experimental colitis in mice. PPAR beta/delta can negatively regulate inflammation and is highly expressed in the epithelial cells of the colon, therefore PPAR beta/delta may also have a role in experimental colitis. In these studies, colitis was induced by dextran sodium sulfate (DSS) treatment in wild-type and PPAR beta/delta-null mice, with and without the PPAR beta/delta specific ligand GW0742. PPAR beta/delta-null mice exhibited increased sensitivity to DSS-induced colitis, as shown by marked differences in body weight loss, colon length, colonic morphology, myeloperoxidase activity and increased expression of mRNAs encoding the inflammatory markers interferon gamma, tumor necrosis factor-alpha, and interleukin-6 compared to similarly treated wild-type mice. Interestingly, these differences were not affected by ligand activation of PPAR beta/delta in either genotype. These studies demonstrate that PPAR beta/delta expression in the colonic epithelium inhibits inflammation and protects against DSS-induced colitis through a ligand-independent mechanism.