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一氧化氮合酶抑制剂N(G)-单甲基-L-精氨酸可抑制脂多糖刺激的人黏附血单核细胞中巨噬细胞炎性蛋白-1α的产生。

Macrophage inflammatory protein-1 alpha production in lipopolysaccharide-stimulated human adherent blood mononuclear cells is inhibited by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine.

作者信息

Mühl H, Dinarello C A

机构信息

Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver 80262, USA.

出版信息

J Immunol. 1997 Nov 15;159(10):5063-9.

PMID:9366434
Abstract

The release of chemokines such as macrophage-inflammatory protein-1 alpha (MIP-1 alpha) from activated macrophages is a crucial step in cell recruitment necessary for establishing local inflammatory responses. To ascertain the importance of the L-arginine/nitric oxide (NO) pathway in LPS-induced MIP-1 alpha release, we stimulated human adherent PBMC with LPS in the presence of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). L-NMMA decreased LPS-induced MIP-1 alpha protein release (45.5% inhibition) and steady state levels of mRNA (48% inhibition) in adherent PBMC. The concentration of L-NMMA for inhibition of MIP-1 alpha release was dependent on the concentration of L-arginine in the cell culture medium, emphasizing the L-arginine-related action of the drug. Most of the MIP-1 alpha release was attributed to the activity of IL-1 and TNF, since coincubation of LPS-stimulated PBMC with IL-1R antagonist and TNF-binding protein abrogated LPS-induced MIP-1 alpha release (by 76.8%). Analysis of cytokine secretion revealed that, in addition to MIP-1 alpha, L-NMMA inhibited the release of mature IL-1 beta (by 70%) and TNF-alpha (by 53%). In contrast, release of macrophage chemoattractant protein-1 was unaffected; IL-10 was augmented (123.4%) by L-NMMA. In the presence of exogenous NO provided by NO donors, LPS-induced MIP-1 alpha release was enhanced. We concluded that endogenous NO acts as a mediator of inflammation. Since IL-10 is a potent anti-inflammatory cytokine, these data also suggest that L-NMMA acts as an anti-inflammatory agent by specifically altering the balance of pro- and anti-inflammatory cytokines released from LPS-stimulated human PBMC.

摘要

活化巨噬细胞释放趋化因子如巨噬细胞炎性蛋白-1α(MIP-1α)是建立局部炎症反应所需细胞募集的关键步骤。为了确定L-精氨酸/一氧化氮(NO)途径在脂多糖(LPS)诱导的MIP-1α释放中的重要性,我们在NO合酶抑制剂N(G)-单甲基-L-精氨酸(L-NMMA)存在的情况下,用LPS刺激人贴壁外周血单核细胞(PBMC)。L-NMMA降低了贴壁PBMC中LPS诱导的MIP-1α蛋白释放(抑制率45.5%)和mRNA的稳态水平(抑制率48%)。抑制MIP-1α释放的L-NMMA浓度取决于细胞培养基中L-精氨酸的浓度,强调了该药物与L-精氨酸相关的作用。大多数MIP-1α释放归因于白细胞介素-1(IL-1)和肿瘤坏死因子(TNF)的活性,因为LPS刺激的PBMC与IL-1受体拮抗剂和TNF结合蛋白共同孵育可消除LPS诱导的MIP-1α释放(76.8%)。细胞因子分泌分析显示,除了MIP-1α外,L-NMMA还抑制成熟IL-1β的释放(70%)和TNF-α的释放(53%)。相反,巨噬细胞趋化蛋白-1的释放未受影响;L-NMMA使IL-10增加(123.4%)。在NO供体提供外源性NO的情况下,LPS诱导的MIP-1α释放增强。我们得出结论,内源性NO作为炎症介质起作用。由于IL-10是一种有效的抗炎细胞因子,这些数据还表明L-NMMA通过特异性改变LPS刺激的人PBMC释放的促炎和抗炎细胞因子的平衡而作为一种抗炎剂起作用。

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