Rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2, PPARγ agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages
Rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2, PPARγ agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages
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DOI：
10.1089/ars.2007.1889
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发表时间：
2008-02-01
影响因子：
6.6
通讯作者：
Rahman, Irfan
中科院分区：
文献类型：
--
作者：
Caito, Samuel;Yang, Se-Ran;Rahman, Irfan
过氧化物酶体增殖物激活受体γ（PPAR γ）配体有可能用作慢性气道疾病的抗炎药。我们假设，香烟烟雾（CS）介导的促炎细胞因子释放将下调单核细胞-巨噬细胞系（MonoMac 6）的合成和天然的PPAR γ配体。令人惊讶的是，用天然PPAR γ配体15-脱氧-δ（12，14）-前列腺素J（2）处理MonoMac 6细胞导致响应TNF-α或CS提取物（CSE）的细胞因子（IL-8）释放增加。然而，暴露于合成激动剂罗格列酮导致TNF-α介导的细胞因子释放减少，而不是CSE。细胞因子释放与核PPAR γ定位相关; CSE减少了位于核中的活化的PPAR γ的量，并形成了作为PPAR γ蛋白羰基的醛加合物。此外，研究表明，在TNF-α暴露条件下，PPAR γ与NF-κ B的RelA/p65亚基相互作用，但这种相互作用被CS暴露破坏，表明CS阻断了这种涉及PPAR γ的重要抗炎途径。因此，这些新的数据表明，天然或合成配体激活的PPAR γ对CS介导的促炎介质释放具有不同的抑制作用。这些数据对设计治疗COPD和肺纤维化的疗法具有意义。
Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPAR gamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPAR gamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-alpha, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPAR gamma localization; CSE reduced the amount of activated PPAR gamma located in the nucleus and formed aldehyde adducts as PPAR gamma protein carbonyls. Furthermore, it was shown that PPAR gamma interacts with the RelA/p65 subunit of NF-kB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPAR gamma. Thus, these new data show that activation of PPAR gamma with natural or synthetic ligands have differential inhibitory effects on CS-mediated pro-inflammatory mediator release. These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis.