Human immunodeficiency virus infection alters tumor necrosis factor alpha production via toll-like receptor-dependent pathways in alveolar macrophages and U1 cells
Human immunodeficiency virus infection alters tumor necrosis factor alpha production via toll-like receptor-dependent pathways in alveolar macrophages and U1 cells
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DOI：
10.1128/jvi.00362-08
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发表时间：
2008-08-01
影响因子：
5.4
通讯作者：
Skolnik, Paul R.
中科院分区：
文献类型：
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作者：
Nicol, Marlynne Q.;Mathys, Jean-Marie;Skolnik, Paul R.
人体免疫缺陷病毒（艾滋病毒）阳性者即使在接受有效的高效抗逆转录病毒治疗后，也易患肺部感染。其原因尚不清楚，但可能涉及先天免疫功能的变化。巨噬细胞的HIV I型感染损害效应子功能，包括细胞因子产生。与健康对照组相比，我们观察到HIV阳性受试者支气管肺泡灌洗液样本中组成性肿瘤坏死因子α（TNF-et）浓度降低，可溶性肿瘤坏死因子受体II（sTNFRII）增加。此外，通过TNF-α/sTNFRII比率测量的净促炎性TNF-α活性随着HIV相关疾病的进展而降低，如通过降低的CD 4细胞计数和增加的HIV RNA（病毒载量）所证明的。由于TNF-α是先天性免疫系统的重要组成部分，并且在Toll样受体（TLR）途径活化后产生，我们假设与肺中TNF-α产生缺陷相关的机制涉及TLR表达改变或TLR信号级联中的缺陷。我们发现减少Toll样受体1（TLRI）和TLR 4的表面表达在HYV感染的UI单核细胞相比，未感染的父母U937细胞系和减少TLR的信息在肺泡巨噬细胞（AM）从HfV阳性受试者。此外，与U937细胞相比，用TLR 1/2配体（PaM 3CYS）或TLR 4配体（脂多糖）刺激导致UI细胞中细胞内磷酸化的细胞外信号调节激酶减少，随后TNF-α的转录和表达减少。来自HIV阳性受试者的AM也显示响应于这些TLR 2和TLR 4配体的TNF-α产生减少。我们推测，HIV感染改变了TLR的表达，随后丝裂原活化蛋白激酶信号传导和细胞因子产生发生变化，最终导致先天免疫应答缺陷，使HIV阳性受试者易受感染。
Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type I infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-et) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-alpha activity, as measured by the TNF-a/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-ot is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-et production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLRI) and TLR4 surface expression in HYV-infected UI monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HfV-positive subjects. In addition, stimulation with TLRI/2 ligand (PaM3CYS) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-ci in UI cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-a production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HfV-positive subjects to infection.