School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India.
Cytokine. 2012 Dec;60(3):778-86. doi: 10.1016/j.cyto.2012.07.036. Epub 2012 Aug 25.
The peroxisome proliferator-activated receptor (PPAR) γ plays an important role in macrophage inflammatory homeostasis. Here we investigate the cross talk between PPARγ and TLR2 signaling pathway in mouse peritoneal macrophages. Real time RT-PCR and immunoblot analysis revealed that peptidoglycan (PGN) treatment of macrophages leads to biphasic effect on PPARγ expression i.e. an early upregulation and a late suppression. Inhibition of ERK MAP kinase by PD98059 abolished the early and rapid induction of PPARγ, while the inhibition of JNK MAP kinase by SP600125 nullifies the late inhibitory effect on the PPARγ expression in a dose-dependent manner. Furthermore, PPARγ knockdown macrophages showed enhanced NF-κB activity after PGN treatment. PGN treatment also enhances PPARγ interaction with p65 as observed by immunoprecipitation. This interaction may inhibit NF-κB (p65) activity as increased nuclear localization of p65 was observed in PPARγ knockdown macrophages after PGN treatment. PPARγ knockdown also increased the PGN-induced inflammatory cytokines (TNF-α, IL-1β, IL-12p40) production. Thus, our observations suggest that PGN induces PPARγ expression which is regulated by MAPKs activation and this enhanced PPARγ in turn attenuate NF-κB activity probably via enhancing p65 nuclear export. These results provide insight into how these pathways could be modulated in inflammatory diseases.
过氧化物酶体增殖物激活受体 (PPAR)γ 在巨噬细胞炎症稳态中发挥重要作用。在这里，我们研究了 PPARγ 和 TLR2 信号通路在小鼠腹腔巨噬细胞中的串扰。实时 RT-PCR 和免疫印迹分析显示，肽聚糖 (PGN) 处理巨噬细胞会导致 PPARγ 表达的双相效应，即早期上调和晚期抑制。用 PD98059 抑制 ERK MAP 激酶可消除 PPARγ 的早期和快速诱导，而用 SP600125 抑制 JNK MAP 激酶则可消除 PPARγ 表达的晚期抑制作用，呈剂量依赖性。此外，PPARγ 敲低巨噬细胞在 PGN 处理后表现出增强的 NF-κB 活性。PGN 处理还增强了 PPARγ 与 p65 的相互作用，如免疫沉淀观察到的那样。这种相互作用可能抑制 NF-κB（p65）活性，因为在 PGN 处理后，PPARγ 敲低巨噬细胞中观察到 p65 的核定位增加。PPARγ 敲低还增加了 PGN 诱导的炎症细胞因子（TNF-α、IL-1β、IL-12p40）的产生。因此，我们的观察结果表明，PGN 诱导 PPARγ 表达，其受 MAPKs 激活的调节，这种增强的 PPARγ 反过来又减弱 NF-κB 活性，可能是通过增强 p65 的核输出。这些结果为这些途径如何在炎症性疾病中被调节提供了深入的了解。
