Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor γ and nuclear factor-κB in macrophages
Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor γ and nuclear factor-κB in macrophages
复制标题
DOI：
10.1111/j.1365-2567.2008.02849.x
复制
发表时间：
2008-11-01
期刊：
影响因子：
6.4
通讯作者：
Thompson, E. Aubrey
中科院分区：
文献类型：
--
作者：
Necela, Brian M.;Su, Weidong;Thompson, E. Aubrey
过氧化物酶体增殖物激活受体γ（PPARγ）在巨噬细胞中表达，在抑制炎症反应中发挥重要作用。脂多糖 (LPS) 可激活 Toll 样受体 4 (TLR4)，降低腹膜巨噬细胞和巨噬细胞系中 PPAR gamma 的表达和功能。此外，用合成的 PPAR γ 配体罗格列酮进行预处理并不能阻止 LPS 介导的 PPAR γ 下调。放线菌酮不会阻断 PPAR γ 表达的抑制，表明 LPS 介导的 PPAR γ 抑制不需要从头合成蛋白质。在 LPS 刺激的巨噬细胞中未观察到 PPAR γ 信使 RNA (mRNA) 的不稳定，表明 LPS 调节 PPAR γ mRNA 的合成。 LPS 对 TLR4 敲除小鼠的巨噬细胞中的 PPAR γ 表达没有影响，而 LPS 抑制已重构以表达功能性 TLR4 的细胞中的 PPAR γ 表达。使用 MEK1/2、p38、JNK 和 AP-1 抑制剂靶向 TLR4 通路，对 LPS 下调 PPAR gamma 没有影响。然而，针对 NEMO、I kappa B 和 NF-kappa B 的抑制剂消除了 LPS 刺激的巨噬细胞中 LPS 介导的 PPAR gamma 下调。我们的数据表明，TLR4 的激活通过 NF-κ B 依赖性机制抑制 PPAR gamma mRNA 合成。巨噬细胞特异性 PPAR γ 敲除细胞的低密度基因组分析表明，PPAR γ 在基础条件下抑制炎症，并且 PPAR γ 表达的丧失足以诱导促炎状态。我们的数据揭示了一个调节反馈回路，其中 PPAR γ 抑制未受刺激的巨噬细胞中 NF-κ B 介导的炎症信号传导；然而，TLR4 激活后，NF-κ B 会降低 PPAR gamma 表达，从而消除 PPAR gamma 在 LPS 刺激的巨噬细胞中的任何潜在抗炎作用。
The peroxisome proliferator-activated receptor gamma (PPAR gamma) is expressed in macrophages and plays an important role in suppressing the inflammatory response. Lipopolysaccharides (LPS), which activate Toll-like receptor 4 (TLR4), reduced PPAR gamma expression and function in peritoneal macrophages and macrophage cell lines. Moreover, pretreatment with the synthetic PPAR gamma ligand, rosiglitazone did not prevent LPS-mediated downregulation of PPAR gamma. Inhibition of PPAR gamma expression was not blocked by cycloheximide, indicating that de novo protein synthesis is not required for LPS-mediated suppression of PPAR gamma. Destabilization of PPAR gamma messenger RNA (mRNA) was not observed in LPS-stimulated macrophages, suggesting that LPS regulates the synthesis of PPAR gamma mRNA. LPS had no effect on PPAR gamma expression in macrophages from TLR4 knockout mice, whereas LPS inhibited PPAR gamma expression in cells that had been reconstituted to express functional TLR4. Targeting the TLR4 pathway with inhibitors of MEK1/2, p38, JNK and AP-1 had no effect on PPAR gamma downregulation by LPS. However, inhibitors that target NEMO, I kappa B and NF-kappa B abolished LPS-mediated downregulation of PPAR gamma in LPS-stimulated macrophages. Our data indicate that activation of TLR4 inhibits PPAR gamma mRNA synthesis by an NF-kappa B-dependent mechanism. Low-density genomic profiling of macrophage-specific PPAR gamma knockout cells indicated that PPAR gamma suppresses inflammation under basal conditions, and that loss of PPAR gamma expression is sufficient to induce a proinflammatory state. Our data reveal a regulatory feedback loop in which PPAR gamma represses NF-kappa B-mediated inflammatory signalling in unstimulated macrophages; however, upon activation of TLR4, NF-kappa B drives down PPAR gamma expression and thereby obviates any potential anti-inflammatory effects of PPAR gamma in LPS-stimulated macrophages.