Endogenous epoxygenases are modulators of monocyte/macrophage activity.
Endogenous epoxygenases are modulators of monocyte/macrophage activity.
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DOI：
10.1371/journal.pone.0026591
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bishop-Bailey D
中科院分区：
文献类型：
--
作者：
Bystrom J;Wray JA;Sugden MC;Holness MJ;Swales KE;Warner TD;Edin ML;Zeldin DC;Gilroy DW;Bishop-Bailey D
花生四烯酸通过三种主要代谢途径代谢，即环氧合酶、脂氧合酶和CYP 450酶系统。与环氧合酶和脂氧合酶不同，CYP 450表氧化酶在单核细胞/巨噬细胞介导的反应中的作用尚不清楚。当在体外转染时，CYP 2 J2是通过核受体过氧化物酶体增殖物激活受体（PPAR）α的抗炎途径的有效激活剂。人单核细胞和巨噬细胞含有过氧化物酶体增殖物激活受体α，在此我们显示它们表达环氧酶CYP 2 J2和CYP 2C 8。使用环氧合酶抑制剂SKF 525 A抑制组成型单核细胞环氧合酶可诱导环氧合酶（考克斯）-2表达和活性以及TNFα的释放，并且可通过添加内源性环氧合酶产物和PPARα配体11，12-环氧二十碳三烯酸（EET）或添加选择性合成PPARα配体GW 7647来逆转。在交替活化（IL-4处理）的单核细胞中，与经典活化细胞相反，环氧合酶抑制减少TNFα释放。环氧合酶可以通过产生超氧阴离子而促炎。在IL-4存在的情况下，SKF 525 A对TNFα的抑制与超氧阴离子产生的减少有关，并由超氧化物歧化酶MnCl 2复制。与这些急性活化研究相似，在单核细胞衍生的巨噬细胞中，环氧合酶抑制可升高M1巨噬细胞TNFα mRNA，并进一步降低M2巨噬细胞TNFα。总之，环氧合酶活性是限制单核细胞活化的重要内源性途径。此外，内源性环氧合酶是免疫调节剂，根据潜在的活化状态调节单核细胞/巨噬细胞活化。
Arachidonic acid is metabolized through three major metabolic pathways, the cyclooxygenase, lipoxygenase and CYP450 enzyme systems. Unlike cyclooxygenase and lipoxygenases, the role of CYP450 epoxygenases in monocyte/macrophage-mediated responses is not known. When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. Human monocytes and macrophages contain PPARα and here we show they express the epoxygenases CYP2J2 and CYP2C8. Inhibition of constitutive monocyte epoxygenases using the epoxygenase inhibitor SKF525A induces cyclooxygenase (COX)-2 expression and activity, and the release of TNFα, and can be reversed by either add back of the endogenous epoxygenase products and PPARα ligand 11,12- epoxyeicosatrienoic acid (EET) or the addition of the selective synthetic PPARα ligand GW7647. In alternatively activated (IL-4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNFα release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNFα by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl2. Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNFα mRNA and further decreases M2 macrophage TNFα. In conclusion, epoxygenase activity represents an important endogenous pathway which limits monocyte activation. Moreover endogenous epoxygenases are immuno-modulators regulating monocyte/macrophage activation depending on the underlying activation state.
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