PRODUCTION OF ANGIOGENIC ACTIVITY BY HUMAN MONOCYTES REQUIRES AN L-ARGININE NITRIC-OXIDE SYNTHASE-DEPENDENT EFFECTOR MECHANISM
PRODUCTION OF ANGIOGENIC ACTIVITY BY HUMAN MONOCYTES REQUIRES AN L-ARGININE NITRIC-OXIDE SYNTHASE-DEPENDENT EFFECTOR MECHANISM
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DOI：
10.1073/pnas.91.10.4190
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发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
KOCH, AE
中科院分区：
文献类型：
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作者：
LEIBOVICH, SJ;POLVERINI, PJ;KOCH, AE
人体单核细胞（mphi）需要细菌内毒素（脂多糖）等物质的刺激才能产生血管生成活性。在这项研究中，我们报告了在缺乏l -精氨酸的情况下，用LPS （5 μ g/ml）刺激M phi大大降低了它们的血管生成活性，这是在大鼠角膜和体外通过人脐静脉内皮细胞（HU-VECs）的趋化性进行的评估。d -精氨酸不能替代l -精氨酸产生血管生成活性。一氧化氮合酶（NO synthase, EC 1.14.13.39）抑制剂n - g -单甲基- l-精氨酸（L-NMMA）和n - g -硝基- l-精氨酸甲酯（L-NAME）在l-精氨酸存在的情况下均抑制lps刺激的m.phi血管生成活性的产生，提示该酶参与了血管生成活性的产生途径。这两种物质都不能直接抑制m.i i衍生的血管生成活性。在不含l -精氨酸的条件下，lps诱导的肿瘤坏死因子α (tnf - α)和白细胞介素8 （IL-8）的产生没有显著降低。同样，L-NMMA和L-NAME在l -精氨酸存在的情况下也没有显著降低lps诱导的M - phi产生这些细胞因子。这些结果表明，依赖于lps刺激的mphi生成血管生成活性需要依赖于l -精氨酸的no合成酶效应机制，该机制可能独立于tnf - α和IL-8的生成。
Human monocytes (M phi) require stimulation with substances such as bacterial endotoxin [LPS (lipopolysaccharide)] to produce angiogenic activity. In this study, we report that stimulation of M phi with LPS (5 mu g/ml) in the absence of L-arginine greatly reduced their production of angiogenic activity, as assessed in vivo in rat corneas and in vitro by chemotaxis of human umbilical vein endothelial cells (HU-VECs). D-Arginine did not substitute for L-arginine in the production of angiogenic activity. The nitric oxide synthase (NO synthase, EC 1.14.13.39) inhibitors N-G-monomethyl-L-arginine (L-NMMA) and N-G-nitro-L-arginine methyl ester (L-NAME) both inhibited the production of angiogenic activity by LPS-stimulated M phi in the presence of L-arginine, suggesting the involvement of this enzyme in the pathway that generates angiogenic activity. Neither of these substances directly inhibited the M phi-derived angiogenic activity. LPS-induced production of the cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) was not significantly reduced when M phi were incubated in the absence of L-arginine. Similarly, L-NMMA and L-NAME did not significantly reduce the LPS-induced production of these cytokines by M phi in the presence of L-arginine. These results suggest that the LPS-stimulation-dependent generation of angiogenic activity by M phi requires an L-arginine-dependent NO-synthase effector mechanism that may be independent of the generation of TNF-alpha and IL-8.