白细胞介素-18在人类自然杀伤细胞死亡中的新作用：系统性自身免疫疾病患者血清水平升高及自然杀伤细胞数量减少

A novel role for interleukin-18 in human natural killer cell death: high serum levels and low natural killer cell numbers in patients with systemic autoimmune diseases.

作者信息

Shibatomi K, Ida H, Yamasaki S, Nakashima T, Origuchi T, Kawakami A, Migita K, Kawabe Y, Tsujihata M, Anderson P, Eguchi K

机构信息

Nagasaki University School of Medicine, Japan.

出版信息

Arthritis Rheum. 2001 Apr;44(4):884-92. doi: 10.1002/1529-0131(200104)44:4<884::AID-ANR145>3.0.CO;2-4.

DOI:10.1002/1529-0131(200104)44:4<884::AID-ANR145>3.0.CO;2-4

PMID:11315928

Abstract

OBJECTIVE

Patients with systemic autoimmune diseases have been reported to have reduced numbers of peripheral blood natural killer (NK) cells compared with healthy subjects. The ability of selected cytokines to trigger NK cell death prompted us to compare the levels of peripheral blood cytokines with the numbers of NK cells in patients with various systemic autoimmune diseases.

METHODS

We used enzyme-linked immunosorbent assays to measure the concentration of selected cytokines (interleukin-18 [IL-18], IL-15, IL-12, IL-2, interferon-gamma [IFNgamma], and tumor necrosis factor alpha [TNFalpha]) in sera from 58 patients with systemic autoimmune diseases and 33 healthy controls. The absolute number of T cells and NK cells in the peripheral blood was measured in parallel using flow cytometry. The ability of selected cytokines to induce NK cell death was then measured using 3,3'-dihexyloxacarbocyanine iodide dye, propidium iodide staining, and caspase 3 activity.

RESULTS

Levels of IL-18, IL-15, IFNgamma, and TNFalpha were elevated in sera from patients with systemic autoimmune diseases compared with normal controls. The percentage of NK cells and natural killer T cells were significantly decreased in the peripheral blood of patients with systemic autoimmune diseases compared with normal controls. Serum concentrations of IL-18, IL-15, and TNFalpha were inversely related to the number of NK cells in both patients and healthy controls. The combination of IL-18 and IL-15 or IL-18 and IL-12 induced NK cell death in vitro. The combination of IL-18 and IL-15 or IL-18 and IL-12 enhanced IFNgamma and TNFalpha production by NK cells in vitro. Cytokine-induced NK cell death is caspase-dependent and is partially blocked by neutralizing antibodies against TNFalpha.

CONCLUSION

High levels of IL-18 and IL-15 are associated with the decreased number of NK cells that is observed in patients with systemic autoimmune diseases.

摘要

目的

据报道，与健康受试者相比，系统性自身免疫性疾病患者外周血自然杀伤（NK）细胞数量减少。特定细胞因子触发NK细胞死亡的能力促使我们比较各种系统性自身免疫性疾病患者外周血细胞因子水平与NK细胞数量。

方法

我们采用酶联免疫吸附测定法，检测了58例系统性自身免疫性疾病患者和33例健康对照者血清中特定细胞因子（白细胞介素-18 [IL-18]、IL-15、IL-12、IL-2、干扰素-γ [IFNγ] 和肿瘤坏死因子α [TNFα]）的浓度。同时使用流式细胞术检测外周血中T细胞和NK细胞的绝对数量。然后使用3,3'-二己基氧杂羰花青碘化物染料、碘化丙啶染色和半胱天冬酶3活性检测特定细胞因子诱导NK细胞死亡的能力。

结果

与正常对照组相比，系统性自身免疫性疾病患者血清中IL-18、IL-15、IFNγ和TNFα水平升高。与正常对照组相比，系统性自身免疫性疾病患者外周血中NK细胞和自然杀伤T细胞的百分比显著降低。患者和健康对照者血清中IL-18、IL-15和TNFα浓度均与NK细胞数量呈负相关。IL-18与IL-15或IL-18与IL-12联合在体外可诱导NK细胞死亡。IL-18与IL-15或IL-18与IL-12联合在体外可增强NK细胞产生IFNγ和TNFα。细胞因子诱导的NK细胞死亡依赖半胱天冬酶，且可被抗TNFα中和抗体部分阻断。