Sumoylation of peroxisome proliferator-activated receptor gamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal from kappaB binding sites mediating transrepression of proinflammatory cytokines.
Sumoylation of peroxisome proliferator-activated receptor gamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal from kappaB binding sites mediating transrepression of proinflammatory cytokines.
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DOI：
10.4049/jimmunol.181.8.5646
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发表时间：
2008-10-15
期刊：
影响因子：
--
通讯作者：
Brüne B
中科院分区：
文献类型：
--
作者：
Jennewein C;Kuhn AM;Schmidt MV;Meilladec-Jullig V;von Knethen A;Gonzalez FJ;Brüne B
专业吞噬细胞有效清除凋亡细胞（AC）对于组织稳态和炎症消退至关重要。巨噬细胞对 AC 做出反应，增加抗炎细胞因子的产生，但促炎介质的释放减少。解释促炎细胞因子形成减弱的机制仍然难以捉摸。我们提供的证据表明，过氧化物酶体增殖物激活受体 γ (PPARγ) 在 AC 激活后可协调抗炎反应。在 LPS 刺激之前将小鼠 RAW264.7 巨噬细胞暴露于 AC，可减少 NFκB 反式激活并降低靶基因表达，例如TNFα 和 IL-6 与对照相比。在过表达 PPARγ 显性失活 (d/n) 突变体的巨噬细胞中，响应 LPS 的 NFκB 反式激活得以恢复，而来自骨髓谱系特异性条件性 PPARγ 敲除小鼠的巨噬细胞证明，PPARγ 传递了由 AC 传递的抗炎反应。表达 PPARγ-Δaa32-250 缺失突变体，我们观察到 NFκB 没有受到抑制。通过分析 aa32-250 内的 PPARγ 结构域结构，我们预计 PPARγ 苏酰化可介导 AC 的抗炎作用。通过突变预测的苏酰化位点 (K77R) 或敲低 SUMO E3 连接酶 PIAS1 来干扰 PPARγ 的苏酰化，消除了 AC 抑制 NFκB 的能力。 ChIP 分析表明，AC 阻止了 LPS 诱导的 TNFα 启动子内 κB 位点核受体辅阻遏物 (NCoR) 的去除。我们得出结论，AC 诱导 PPARγ 苏酰化以减弱 NCoR 的去除，从而阻断 NFκB 的反式激活。通过降低促炎细胞因子的产生，这有助于响应 AC 的巨噬细胞发生抗炎表型转变。
Efficient clearance of apoptotic cells (AC) by professional phagocytes is crucial for tissue homeostasis and resolution of inflammation. Macrophages respond to AC with an increase in anti-inflammatory cytokine production, but a diminished release of pro-inflammatory mediators. Mechanisms to explain attenuated pro-inflammatory cytokine formation remain elusive. We provide evidence that peroxisome proliferator-activated receptor γ (PPARγ) coordinates anti-inflammatory responses following its activation by AC. Exposing murine RAW264.7 macrophages to AC prior to LPS-stimulation, reduced NFκB transactivation and lowered target gene expression of e.g. TNFα and IL-6 compared to controls. In macrophages overexpressing a dominant negative (d/n) mutant of PPARγ, NFκB transactivation in response to LPS was restored, while macrophages from myeloid lineage-specific conditional PPARγ knockout mice proved that PPARγ transmitted an anti-inflammatory response, delivered by AC. Expressing a PPARγ-Δaa32-250 deletion mutant, we observed no inhibition of NFκB. Analyzing the PPARγ domain structures within aa32-250, we anticipated PPARγ sumoylation in mediating the anti-inflammatory effect in response to AC. Interfering with sumoylation of PPARγ by mutating the predicted sumoylation site (K77R), or knockdown of the SUMO E3 ligase PIAS1, eliminated the ability of AC to suppress NFκB. ChIP analysis demonstrated that AC prevented the LPS-induced removal of nuclear receptor co-repressor (NCoR) from the κB site within the TNFα promoter. We conclude that AC induce PPARγ sumoylation to attenuate the removal of NCoR, thereby blocking transactivation of NFκB. This contributes to an anti-inflammatory phenotype shift in macrophages responding to AC, by lowering pro-inflammatory cytokine production.
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