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首页> 外文期刊>Cytokine >Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting
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Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting

机译：抗凝血酶III，但不是C1酯酶抑制剂，可降低离体全血环境中脂多糖刺激的人单核细胞的炎症反应

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摘要

In order to examine the immunomodulatory effects of antithrombin III (AT-III) and C1 esterase inhibitor (C1-INH) in human monocytes, we investigated the intracellular expression of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in an ex-vivo laboratory study in a whole blood setting. Heparinized whole blood samples from 23 healthy male and female volunteers (mean age: 27±7years) were pre-incubated with clinically relevant concentrations of AT-III (n=11) and C1-INH (n=12), then stimulated with 0.2ng/mL lipopolysaccharide (LPS) for 3h. After phenotyping CD14+ monocytes, intracellular expression of IL-6, IL-8, and TNF-α was assessed using flow cytometry. In addition, 12 whole blood samples (AT-III and C1-INH, n=6 each) were examined using hirudin for anticoagulation; all samples were processed in the same way. To exclude cytotoxicity effects, 7-amino-actinomycin D and Nonidet P40 staining were used to investigate probes. This study is the first to demonstrate the influence of C1-INH and AT-III on the monocytic inflammatory response in a whole blood setting, which mimics the optimal physiological setting. Cells treated with AT-III exhibited significant downregulation of the proportion of gated CD14+ monocytes for IL-6 and IL-8, in a dose-dependent manner; downregulation for TNF-α did not reach statistical significance. There were no significant effects on mean fluorescence intensity (MFI). In contrast, C1-INH did not significantly reduce the proportion of gated CD14+ monocytes or the MFI regarding IL-6, TNF-α, and IL-8. When using hirudin for anticoagulation, no difference in the anti-inflammatory properties of AT-III and C1-INH in monocytes occurs. Taken together, in contrast to TNF-α, IL-6 and IL-8 were significantly downregulated in monocytes in an ex-vivo setting of human whole blood when treated with AT-III. This finding implicates monocytes as an important point of action regarding the anti-inflammatory properties of AT-III in sepsis. C1-INH was unable to attenuate the monocytic response, which supports the hypothesis that other cellular components in whole blood (e.g., neutrophils) might be responsible for the known effects of C1-INH in inflammation.
机译：为了检查抗凝血酶III（AT-III）和C1酯酶抑制剂（C1-INH）在人单核细胞中的免疫调节作用，我们研究了白细胞介素（IL）-6，IL-8和肿瘤坏死因子（ TNF）-α在全血环境下的体外实验研究中。将23名健康的男性和女性志愿者的肝素化全血样品（平均年龄：27±7岁）与临床上相关浓度的AT-III（n = 11）和C1-INH（n = 12）进行预孵育，然后用0.2刺激ng / mL脂多糖（LPS）3h。在对CD14 +单核细胞进行表型分析后，使用流式细胞仪评估了IL-6，IL-8和TNF-α的细胞内表达。另外，使用水rud素检查了12种全血样品（AT-III和C1-INH，每个n = 6）的抗凝性;所有样品都以相同的方式处理。为了排除细胞毒性作用，使用7-氨基放线菌素D和Nonidet P40染色来研究探针。这项研究首次证明了C1-INH和AT-III对全血环境中单核细胞炎性反应的影响，模拟了最佳的生理环境。用AT-III处理的细胞对IL-6和IL-8的门控CD14 +单核细胞比例呈剂量依赖性显着下调。 TNF-α的下调没有达到统计学意义。对平均荧光强度（MFI）没有显着影响。相反，对于IL-6，TNF-α和IL-8，C1-INH并未显着降低门控CD14 +单核细胞或MFI的比例。当使用水rud素进行抗凝时，单核细胞中AT-III和C1-INH的抗炎特性没有差异。两者合计，与TNF-α相反，当用AT-III治疗时，在人全血的离体设置中，IL-6和IL-8在单核细胞中显着下调。这一发现暗示单核细胞是脓毒症中AT-III抗炎特性的重要作用点。 C1-INH不能减弱单核细胞反应，这支持了这样的假设，即全血中的其他细胞成分（例如嗜中性粒细胞）可能是导致C1-INH炎症的已知作用的原因。

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