Ahmad Rasheed, Sindhu Sardar T A, Toma Emil, Morisset Richard, Ahmad Ali
Laboratory of Immunovirology, Pediatric Research Center, University of Montreal and Sainte-Justine Hospital, 3175 Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5.
J Virol. 2002 Dec;76(24):12448-56. doi: 10.1128/jvi.76.24.12448-12456.2002.
Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18) was rediscovered as a proinflammatory cytokine related to the IL-1 family of cytokines that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Despite its importance in inducing and regulating immune responses, relatively little is known about its production in HIV infection. We report here significantly (P < 0.05) elevated levels of this cytokine in the sera of human immunodeficiency virus (HIV)-infected/AIDS patients compared to those of HIV-seronegative healthy persons. Surprisingly, the peripheral blood mononuclear cells (PBMC) from HIV-infected/AIDS patients were compromised in the ability to upregulate IL-18 gene expression and produce this cytokine with and without lipopolysaccharide (LPS) stimulation. A significant positive correlation (P < 0.05) existed between the concentration of IL-18 in serum and its production from PBMC of HIV-seronegative healthy individuals but not those of HIV-infected/AIDS patients. Furthermore, the patients' PBMC expressed relatively reduced levels of activated caspase-1 constitutively as well as in response to LPS stimulation. Our data suggest the involvement of transforming growth factor beta (TGF-beta) in suppressing IL-18 production from the patients' PBMC for the following reasons. (i) In in vitro studies it suppressed the production of IL-18 from PBMC. (ii) Its levels were significantly higher in the plasma of patients compared to that of control subjects. (iii) A significant negative correlation existed between the concentrations of TGF-beta in plasma and of IL-18 in serum of the patients. The elevated levels of IL-18 in the serum of HIV-infected individuals may contribute to AIDS pathogenesis, whereas its compromised production from their PBMC in response to stimuli may reduce their innate defense to opportunistic intracellular pathogens.
白细胞介素-18（IL-18）最初被鉴定为γ干扰素诱导因子，后来又被重新发现是一种与IL-1细胞因子家族相关的促炎细胞因子，在针对病毒和细胞内病原体的固有免疫和适应性免疫反应中均发挥重要作用。尽管它在诱导和调节免疫反应中很重要，但关于其在HIV感染中的产生情况却知之甚少。我们在此报告，与HIV血清阴性的健康人相比，人类免疫缺陷病毒（HIV）感染/艾滋病患者血清中这种细胞因子的水平显著升高（P < 0.05）。令人惊讶的是，HIV感染/艾滋病患者的外周血单个核细胞（PBMC）在有或无脂多糖（LPS）刺激的情况下，上调IL-18基因表达并产生这种细胞因子的能力均受到损害。HIV血清阴性健康个体血清中IL-18的浓度与其PBMC产生IL-18之间存在显著正相关（P < 0.05），而HIV感染/艾滋病患者则不存在这种相关性。此外，患者的PBMC在组成性以及对LPS刺激的反应中，活化的半胱天冬酶-1表达水平相对降低。我们的数据表明转化生长因子β（TGF-β）参与抑制患者PBMC产生IL-18，原因如下：（i）在体外研究中，它抑制了PBMC产生IL-18；（ii）患者血浆中其水平显著高于对照组；（iii）患者血浆中TGF-β的浓度与血清中IL-18的浓度之间存在显著负相关。HIV感染者血清中IL-18水平升高可能有助于艾滋病的发病机制，而其PBMC对刺激产生IL-18的能力受损可能会降低他们对机会性细胞内病原体的固有防御能力。
