Peroxisome proliferator-activated receptor-gamma regulates the expression of alveolar macrophage macrophage colony-stimulating factor.
Peroxisome proliferator-activated receptor-gamma regulates the expression of alveolar macrophage macrophage colony-stimulating factor.
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DOI：
10.4049/jimmunol.181.1.235
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Culver DA
中科院分区：
文献类型：
--
作者：
Bonfield TL;Thomassen MJ;Farver CF;Abraham S;Koloze MT;Zhang X;Mosser DM;Culver DA
巨噬细胞CSF（M-CSF）调节单核细胞分化、活化和泡沫细胞形成。我们已经观察到它在人肺泡蛋白沉积症（PAP）和GM-CSF敲除小鼠（PAP的小鼠模型）中升高。过氧化物酶体增殖物激活受体-γ（过氧化物酶体增殖物激活受体-γ）是M-CSF的一种潜在调节因子，在人PAP和GM-CSF敲除小鼠中均存在严重缺陷。为了研究PPARγ在肺泡巨噬细胞稳态中的作用，我们使用Lys-Cre方法敲除floxed PPARγ基因，产生了骨髓特异性PPARγ敲除小鼠。与GM-CSF缺陷小鼠相似，肺泡巨噬细胞PPARγ缺失导致16周龄小鼠出现类似PAP的肺病理学，沿着过量M-CSF基因表达和分泌。在离体野生型肺泡巨噬细胞中，我们观察到M-CSF本身能够诱导类似于PAP中所见的泡沫细胞形成。在RAW 264.7细胞中，过表达的PPARγ阻止了LPS刺激的M-CSF的产生，这种作用被特异性的PPARγ拮抗剂GW 9662所消除。使用蛋白酶体抑制剂MG-132或PPARγ激动剂吡格列酮可阻止LPS介导的M-CSF诱导。通过染色质免疫沉淀，我们发现PPARγ能够通过转录抑制NF-κB结合在启动子上来调节M-CSF。凝胶迁移试验证实，吡格列酮能够阻断NF-κB结合。综上所述，这些数据表明，M-CSF是肺泡巨噬细胞稳态的重要介质，并且M-CSF产生的转录控制受NF-κB和PPARγ调节。
Macrophage CSF (M-CSF) regulates monocyte differentiation, activation, and foam cell formation. We have observed that it is elevated in human pulmonary alveolar proteinosis (PAP) and in the GM-CSF knockout mouse, a murine model for PAP. A potential regulator of M-CSF, peroxisome proliferator-activated receptor-γ (PPARγ), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPARγ in alveolar macrophage homeostasis, we generated myeloidspecific PPARγ knockout mice using the Lys-Cre method to knock out the floxed PPARγ gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPARγ resulted in development of lung pathology resembling PAP in 16-wk-old mice, along with excess M-CSF gene expression and secretion. In ex vivo wild-type alveolar macrophages, we observed that M-CSF itself is capable of inducing foam cell formation similar to that seen in PAP. Overexpression of PPARγ prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPARγ antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPARγ agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPARγ is capable of regulating M-CSF through transrepression of NF-κB binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-κB binding. Taken together, these data suggest that M-CSF is an important mediator of alveolar macrophage homeostasis, and that transcriptional control of M-CSF production is regulated by NF-κB and PPARγ.
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影响因子：
4.9
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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DOI：
10.1165/rcmb.2003-0148oc
发表时间：
2003-12-01
影响因子：
6.4
作者：
Bonfield, TL;Farver, CF;Thomassen, MJ
通讯作者：
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