Alhetheel Abdulkarim, Yakubtsov Yuriy, Abdkader Khaled, Sant Nadia, Diaz-Mitoma Francisco, Kumar Ashok, Kryworuchko Marko
Infectious Disease and Vaccine Research Centre, Children's Hospital of Eastern Ontario - Research Institute, Canada.
AIDS. 2008 Jun 19;22(10):1137-44. doi: 10.1097/QAD.0b013e3283013d42.
Monocytes/macrophages play a major role in inflammation and pathogen clearance. However, chronic immune activation observed during HIV infection may also cause cellular dysfunction and tissue pathology. Indeed, several defects have been reported in these cells during HIV infections. As cytokine responsiveness via the signal transducer and activator of transcription (STAT1) signaling pathway is critical for these functions, we hypothesized that its activation in monocytes from HIV-positive patients may be disrupted.
To evaluate cytokine-dependent STAT signaling in monocytes from HIV-positive patients and study the biological impact and molecular mechanisms responsible for the alterations in the interferon (IFN)-gamma-induced STAT1 pathway observed.
Monocytes from chronically infected HIV-positive patients on and off antiretroviral therapy were assayed respectively for STAT activation, apoptosis, and other downstream effects by flow cytometry, real-time PCR and enzyme-linked immunosorbent assay.
Unlike IFN-alpha, interleukin-10, granulocyte macrophage colony-stimulating factor, and interleukin-4, only IFN-gamma-induced STAT1 activation was upregulated in monocytes from off-therapy patients compared with those on antiretroviral therapy and HIV-negative controls, correlating with increased total STAT1 expression. Among the IFN-gamma responsive genes (IRF-1, CXCL9, CXCL10) studied, differential effects were observed, likely reflecting the more complex regulatory control over their expression. Interestingly, spontaneous monocyte apoptosis was elevated in HIV-positive patients off-therapy compared with HIV-negative controls and correlated with STAT1 expression. IFN-gamma-induced apoptosis was also increased and persisted despite seemingly effective antiretroviral therapy.
Amplification of STAT1 signaling and apoptosis may reflect the chronic nature of immune activation in HIV-positive patients and contribute to the functional impairment observed in monocytes through the course of the disease.
单核细胞/巨噬细胞在炎症反应和病原体清除中起主要作用。然而，在HIV感染过程中观察到的慢性免疫激活也可能导致细胞功能障碍和组织病理变化。事实上，在HIV感染期间，这些细胞已被报道存在多种缺陷。由于通过信号转导和转录激活因子（STAT1）信号通路的细胞因子反应性对这些功能至关重要，我们推测HIV阳性患者单核细胞中该通路的激活可能受到破坏。
评估HIV阳性患者单核细胞中细胞因子依赖性STAT信号传导，并研究导致所观察到的干扰素（IFN）-γ诱导的STAT1通路改变的生物学影响和分子机制。
分别通过流式细胞术、实时聚合酶链反应和酶联免疫吸附测定法，对接受和未接受抗逆转录病毒治疗的慢性HIV感染阳性患者的单核细胞进行STAT激活、凋亡及其他下游效应的检测。
与IFN-α、白细胞介素-10、粒细胞巨噬细胞集落刺激因子和白细胞介素-4不同，与接受抗逆转录病毒治疗的患者及HIV阴性对照相比，未接受治疗的患者单核细胞中仅IFN-γ诱导的STAT1激活上调，这与总STAT1表达增加相关。在所研究的IFN-γ反应性基因（IRF-1、CXCL9、CXCL10）中，观察到了不同的效应，这可能反映了对其表达更为复杂的调控。有趣的是，未接受治疗的HIV阳性患者的单核细胞自发凋亡较HIV阴性对照升高，且与STAT1表达相关。尽管抗逆转录病毒治疗看似有效，但IFN-γ诱导的凋亡也增加且持续存在。
STAT1信号传导的增强和凋亡可能反映了HIV阳性患者免疫激活的慢性本质，并在疾病过程中导致单核细胞出现功能损害。
