Iannello Alexandre, Samarani Suzanne, Debbeche Olfa, Ahmad Rasheed, Boulassel Mohamed-Rachid, Tremblay Cécile, Toma Emil, Routy Jean-Pierre, Ahmad Ali
Department of Microbiology and Immunology, Laboratory of Innate Immunity, CHU-Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
J Virol. 2009 Jun;83(12):5999-6010. doi: 10.1128/JVI.02350-08. Epub 2009 Apr 1.
We had shown earlier that the concentrations of circulating interleukin-18 (IL-18) are increased significantly in human immunodeficiency virus (HIV)-infected persons compared to HIV-seronegative healthy subjects. In the present study, we investigated the consequences of these elevated levels of IL-18 on natural killer (NK) cells and the immunopathogenesis of AIDS. We show here an inverse correlation between IL-18 concentrations and absolute numbers of various subsets of NK cells in infected persons. Recombinant human IL-18 caused increased death of a human NK cell line, as well as of primary human NK cells in vitro. The IL-18-mediated cell death was dependent upon Fas-FasL interactions and tumor necrosis factor alpha. IL-18 induced the expression of FasL on NK cells, increased the transcription from the human FasL promoter, reduced the expression of Bcl-X(L) in NK cells, and increased their sensitivity to FasL-mediated cell death. These results suggest that increased IL-18 concentrations present in the circulation of HIV-infected persons contribute to the immunopathogenesis of AIDS by altering NK cell homeostasis.
我们之前已经表明，与HIV血清阴性的健康受试者相比，人类免疫缺陷病毒（HIV）感染者循环中白细胞介素-18（IL-18）的浓度显著升高。在本研究中，我们调查了这些升高的IL-18水平对自然杀伤（NK）细胞的影响以及艾滋病的免疫发病机制。我们在此展示了感染者中IL-18浓度与NK细胞各亚群绝对数量之间的负相关。重组人IL-18导致人NK细胞系以及体外原代人NK细胞的死亡增加。IL-18介导的细胞死亡依赖于Fas-FasL相互作用和肿瘤坏死因子α。IL-18诱导NK细胞上FasL的表达，增加人FasL启动子的转录，降低NK细胞中Bcl-X(L)的表达，并增加它们对FasL介导的细胞死亡的敏感性。这些结果表明，HIV感染者循环中升高的IL-18浓度通过改变NK细胞稳态而促成艾滋病的免疫发病机制。
