Mono-2-ethylhexylphthalate (MEHP) induces TNF-α release and macrophage differentiation through different signalling pathways in RAW264.7 cells
Mono-2-ethylhexylphthalate (MEHP) induces TNF-α release and macrophage differentiation through different signalling pathways in RAW264.7 cells
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DOI：
10.1016/j.toxlet.2011.11.016
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发表时间：
2012-02-25
影响因子：
3.5
通讯作者：
Becher, Rune
中科院分区：
文献类型：
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作者：
Bolling, Anette Kocbach;Ovrevik, Johan;Becher, Rune
流行病学研究表明，室内邻苯二甲酸酯暴露与儿童和成人哮喘发病率和严重程度增加有关，炎症效应被认为是一种可能的机制。最近的研究报告，邻苯二甲酸酯可以激活促分裂原活化蛋白（MAP）激酶p38和各种过氧化物酶体增殖物激活受体（PPAR）亚型。在这里，我们确认和扩展这些发现，通过调查可能的信号通路激活的小鼠单核细胞-巨噬细胞系RAW 264.7，使用单-2-乙基己基邻苯二甲酸酯（MEHP）作为模型化合物。MEHP暴露（0.3-1.0 mM）3小时增加了肿瘤坏死因子（TNF）-α的释放，并将细胞形态改变为细长的梭形外观，类似于更分化的抗炎巨噬细胞（M2）。这伴随着巨噬细胞分化标志物CD 163的表达增加。Western分析显示暴露30分钟后p38和Akt磷酸化。使用特异性抑制剂的实验表明，MEHP诱导的p38和磷酸肌醇-3（P13）激酶/Akt通路的激活参与了TNF-α的释放;而只有PI 3激酶似乎参与了分化。相比之下，PPARalpha和gamma抑制剂减少分化，但不影响TNF-α的释放。总之，MEHP诱导细胞因子释放并触发RAW264.7细胞分化，可能分化为M2样巨噬细胞，但这些反应似乎涉及不同的信号通路。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Epidemiological studies have associated indoor phthalate exposure with increased incidences and severity of asthma in children and adults, and inflammatory effects have been suggested as a possible mechanism. Recent studies report that phthalates may activate mitogen-activated protein (MAP) kinase p38 and various peroxisome proliferator-activated receptor (PPAR) isoforms. Here we confirm and extend these findings by investigating possible signalling pathways activated in the murine monocyte-macrophage cell line RAW264.7, using mono-2-ethylhexylphthalate (MEHP) as a model compound. MEHP exposure (0.3-1.0 mM) for 3h increased tumour necrosis factor (TNF)-alpha release and changed the cellular morphology into elongated spindle-like appearance, resembling more differentiated anti-inflammatory macrophages (M2). This was accompanied by increased expression of the macrophage differentiation marker CD163. Western analysis showed phosphorylation of p38 and Akt after 30 min exposure. Experiments using specific inhibitors suggested that MEHP-induced activation of both p38 and the phosphoinositide-3 (P13) kinase/Akt pathway were involved in the release of TNF-alpha; whereas only PI3kinase seemed to be involved in differentiation. In contrast, inhibitors of PPAR alpha and gamma reduced differentiation, but did not affect TNF-alpha release. In conclusion, MEHP induced cytokine release and triggered differentiation of RAW264.7 cells, possibly into M2-like macrophages, but different signalling pathways appear to be involved in these responses. (C) 2011 Elsevier Ireland Ltd. All rights reserved.