Heydeck D, Thomas L, Schnurr K, Trebus F, Thierfelder W E, Ihle J N, Kühn H
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin.
Blood. 1998 Oct 1;92(7):2503-10.
When human monocytes or alveolar macrophages are cultured in the presence of interleukin (IL)-4 or IL-13, the expression of the reticulocyte-type 15-lipoxygenase is induced. In mice a 15-lipoxygenase is not expressed, but a leukocyte-type 12-lipoxygenase is present in peritoneal macrophages. To investigate whether both lipoxygenase isoforms exhibit a similar regulatory response toward cytokine stimulation, we studied the regulation of the leukocyte-type 12-lipoxygenase of murine peritoneal macrophages by interleukins and found that the activity of this enzyme is upregulated in a dose-dependent manner when the cells were cultured in the presence of the IL-4 or IL-13 but not by IL-10. When peripheral murine monocytes that do not express the lipoxygenase were treated with IL-4 expression of 12/15-lipoxygenase mRNA was induced, suggesting pretranslational control mechanisms. In contrast, no upregulation of the lipoxygenase activity was observed when the macrophages were prepared from homozygous STAT6-deficient mice. Peritoneal macrophages of transgenic mice that systemically overexpress IL-4 exhibited a threefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals. A similar upregulation of 12-lipoxygenase activity was detected in heart, spleen, and lung of the transgenic animals. Moreover, a strong induction of the enzyme was observed in red cells during experimental anemia in mice. The data presented here indicate that (1) the 12-lipoxygenase activity of murine macrophages is upregulated in vitro and in vivo by IL-4 and/or IL-13, (2) this upregulation requires expression of the transcription factor STAT6, and (3) the constitutive expression of the enzyme appears to be STAT6 independent. The cytokine-dependent upregulation of the murine macrophage 12-lipoxygenase and its induction during experimental anemia suggests its close relatedness with the human reticulocyte-type 15-lipoxygenase despite their differences in the positional specificity of arachidonic acid oxygenation.
当人单核细胞或肺泡巨噬细胞在白细胞介素（IL）-4或IL-13存在的情况下培养时，网织红细胞型15-脂氧合酶的表达被诱导。在小鼠中，不表达15-脂氧合酶，但在腹膜巨噬细胞中存在白细胞型12-脂氧合酶。为了研究这两种脂氧合酶同工型对细胞因子刺激是否表现出相似的调节反应，我们研究了白细胞介素对小鼠腹膜巨噬细胞白细胞型12-脂氧合酶的调节，发现当细胞在IL-4或IL-13存在的情况下培养时，该酶的活性以剂量依赖的方式上调，但不受IL-10的影响。当用IL-4处理不表达脂氧合酶的外周小鼠单核细胞时，诱导了12/15-脂氧合酶mRNA的表达，提示存在翻译前控制机制。相反，当从纯合STAT6缺陷小鼠制备巨噬细胞时，未观察到脂氧合酶活性的上调。全身过表达IL-4的转基因小鼠的腹膜巨噬细胞表现出比对照动物制备的细胞高三到四倍的12-脂氧合酶活性。在转基因动物的心脏、脾脏和肺中检测到12-脂氧合酶活性的类似上调。此外，在小鼠实验性贫血期间，红细胞中观察到该酶的强烈诱导。此处呈现的数据表明：（1）小鼠巨噬细胞的12-脂氧合酶活性在体外和体内被IL-4和/或IL-13上调；（2）这种上调需要转录因子STAT6的表达；（3）该酶的组成型表达似乎不依赖于STAT6。小鼠巨噬细胞12-脂氧合酶的细胞因子依赖性上调及其在实验性贫血期间的诱导表明，尽管它们在花生四烯酸氧化的位置特异性上存在差异，但它与人网织红细胞型15-脂氧合酶密切相关。
