Modolell M, Corraliza I M, Link F, Soler G, Eichmann K
Max-Planck-Institut für Immunbiologie, Freiburg, Germany.
Eur J Immunol. 1995 Apr;25(4):1101-4. doi: 10.1002/eji.1830250436.
Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the amino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline. NO is important in the bactericidal and cytotoxic activities of macrophages. An equivalent functional role of arginase and its products is not known. We tested the induction of arginase in bone marrow-derived macrophages by endogenous mediators that are known to induce NO synthase, such as interferon-gamma (IFN-gamma), or suppress the induction of this enzyme, such as interleukin (IL)-4, IL-10, and prostaglandin E2 (PGE2). We find that PGE2 and the TH2 cytokines IL-4 and IL-10 are potent inducers of arginase. In contrast, the TH1 cytokine IFN-gamma does not induce arginase. Simultaneous application of both types of mediators leads to reduced induction of both arginase and NO synthase. Exposure of macrophage cultures to inducers of NO synthase exhausts their ability to respond subsequently to inducers of arginase. Conversely, exposure of the cells to inducers of arginase exhausts their ability to respond subsequently to inducers of NO synthase. The results are consistent with a competition of both enzymes for their substrate, L-arginine, with a reciprocal inhibition in the induction of both enzymes, or a combination of both phenomena. The enzymes NO synthase and arginase appear to define two alternate functional states of macrophages, induced by TH1 and TH2 cytokines, respectively.
用脂多糖激活可诱导巨噬细胞产生精氨酸酶和一氧化氮（NO）合酶。这两种酶都将氨基酸L-精氨酸用作底物，L-精氨酸既可以被精氨酸酶水解为尿素和鸟氨酸，也可以被NO合酶氧化为NO和瓜氨酸。NO在巨噬细胞的杀菌和细胞毒性活性中很重要。精氨酸酶及其产物的等效功能作用尚不清楚。我们测试了已知可诱导NO合酶的内源性介质（如干扰素-γ（IFN-γ））或抑制该酶诱导的介质（如白细胞介素（IL）-4、IL-10和前列腺素E2（PGE2））对骨髓来源巨噬细胞中精氨酸酶的诱导作用。我们发现PGE2以及TH2细胞因子IL-4和IL-10是精氨酸酶的有效诱导剂。相比之下，TH1细胞因子IFN-γ不会诱导精氨酸酶。同时应用这两种介质会导致精氨酸酶和NO合酶的诱导作用均降低。将巨噬细胞培养物暴露于NO合酶诱导剂会耗尽其随后对精氨酸酶诱导剂作出反应的能力。相反，将细胞暴露于精氨酸酶诱导剂会耗尽其随后对NO合酶诱导剂作出反应的能力。这些结果与两种酶对其底物L-精氨酸的竞争一致，两种酶的诱导存在相互抑制，或者是这两种现象的组合。NO合酶和精氨酸酶似乎分别定义了由TH1和TH2细胞因子诱导的巨噬细胞的两种交替功能状态。
