Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: Role of peripheral blood mononuclear cells and implications for AIDS pathogenesis
Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: Role of peripheral blood mononuclear cells and implications for AIDS pathogenesis
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DOI：
10.1128/jvi.76.24.12448-12456.2002
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发表时间：
2002-12-01
影响因子：
5.4
通讯作者：
Ahmad, A
中科院分区：
文献类型：
--
作者：
Ahmad, R;Sindhu, STA;Ahmad, A
白细胞介素-18（IL-18）最初被鉴定为γ干扰素诱导因子，被重新发现为与细胞因子的IL-1家族相关的促炎细胞因子，其在针对病毒和细胞内病原体的先天性和适应性免疫应答中起重要作用。尽管它在诱导和调节免疫反应中的重要性，但对其在HIV感染中的产生知之甚少。我们在此报道，与HIV血清阴性的健康人相比，HIV感染者/AIDS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，来自HIV感染/AIDS患者的外周血单核细胞（PBMC）在有和没有脂多糖（LPS）刺激的情况下上调IL-18基因表达和产生这种细胞因子的能力受到损害。HIV阴性健康人血清IL-18水平与PBMC IL-18水平呈显著正相关（P < 0.05），而HIV感染者/AIDS患者血清IL-18水平与PBMC IL-18水平无相关性。此外，患者的PBMC表达相对降低水平的活化半胱天冬酶-1组成性以及响应于LPS刺激。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PBMC产生IL-18。(ii)其水平在患者血浆中显著高于对照受试者。(iii)患者血浆TGF-β与血清IL-18浓度呈显著负相关。HIV感染者血清中IL-18水平的升高可能与AIDS发病机制有关，而其PBMC对刺激的反应性降低可能降低其对机会性细胞内病原体的先天防御。
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.