Division of Clinical Chemistry and Biochemistry, Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Atherosclerosis. 2012 Nov;225(1):121-7. doi: 10.1016/j.atherosclerosis.2012.07.022. Epub 2012 Aug 23.
Atherosclerosis is a chronic disease characterized by two main features, lipid retention and inflammation. The 12/15-lipoxygenases play a two-faced role in atherosclerosis with pro-inflammatory effects through oxidation of LDL and anti-inflammatory effects through lipid mediator synthesis. In cells involved in atherosclerosis the 12-lipoxygenase ALOX12 and the two 15-lipoxygenases, ALOX15 and ALOX15B may be expressed but their expression has not yet been investigated in detail.
To investigate the regulation of ALOX12, ALOX15 and ALOX15B in human macrophages we measured basal mRNA and protein expression during differentiation of monocytes to macrophages and stimulated expression in macrophages.
The results show an increase of ALOX15B during the differentiation of monocytes to macrophages, while the expression of ALOX12 and ALOX15 remains on the same low level. Stimulation of macrophages with a set of cytokines and with hypoxia revealed that IL-4, IL-13, LPS and hypoxia further increase the ALOX15B mRNA. Western blot analysis showed that IL-4, LPS and hypoxia increase the ALOX15B protein expression, whereas IL-13 has no effect on the protein levels. IL-4 and IL-13 also enhance ALOX15 mRNA and protein expression, whereas none of the stimuli has an impact on ALOX12 expression.
In summary, these data suggest that ALOX15B is the mainly expressed 12/15-lipoxygenase in human macrophages and that its expression is induced by IL-4, LPS and hypoxia. IL-4 and IL-13 also increase the expression of ALOX15, however, only IL-4 stimulation seems to drive ALOX15 expression to levels higher than the basal expression of ALOX15B. Hence, ALOX15B may play a major role in human atherosclerosis.
动脉粥样硬化是一种以脂质蓄积和炎症为两大特征的慢性疾病。12/15-脂氧合酶在动脉粥样硬化中扮演着两面派的角色，通过 LDL 的氧化发挥促炎作用，通过脂质介质的合成发挥抗炎作用。在动脉粥样硬化相关细胞中，12-脂氧合酶 ALOX12 和两种 15-脂氧合酶，ALOX15 和 ALOX15B 可能会表达，但它们的表达尚未得到详细研究。
为了研究人巨噬细胞中 ALOX12、ALOX15 和 ALOX15B 的调控，我们在单核细胞分化为巨噬细胞的过程中测量了基础 mRNA 和蛋白表达，并刺激了巨噬细胞的表达。
结果显示，在单核细胞分化为巨噬细胞的过程中，ALOX15B 的表达增加，而 ALOX12 和 ALOX15 的表达仍保持在较低水平。用一组细胞因子和缺氧刺激巨噬细胞，结果表明，IL-4、IL-13、LPS 和缺氧进一步增加 ALOX15B 的 mRNA。Western blot 分析表明，IL-4、LPS 和缺氧增加 ALOX15B 蛋白表达，而 IL-13 对蛋白水平没有影响。IL-4 和 IL-13 也增强 ALOX15 的 mRNA 和蛋白表达，而没有一种刺激物对 ALOX12 的表达有影响。
总之，这些数据表明，ALOX15B 是人类巨噬细胞中主要表达的 12/15-脂氧合酶，其表达受 IL-4、LPS 和缺氧的诱导。IL-4 和 IL-13 也增加了 ALOX15 的表达，然而，只有 IL-4 刺激似乎能将 ALOX15 的表达提高到高于 ALOX15B 的基础表达水平。因此，ALOX15B 可能在人类动脉粥样硬化中发挥主要作用。
