PDGF synergistically enhances IFN-γ-induced expression of CXCL10 in blood-derived macrophages:: Implications for HIV dementia
PDGF synergistically enhances IFN-γ-induced expression of CXCL10 in blood-derived macrophages:: Implications for HIV dementia
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DOI：
10.4049/jimmunol.179.5.2722
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Buch, Shilpa
中科院分区：
文献类型：
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作者：
Dhillon, Navneet Kaur;Peng, Fuwang;Buch, Shilpa
越来越多的累积证据表明，在CNS中释放炎性介质的活化单核吞噬细胞（巨噬细胞/小胶质细胞）比脑中的实际病毒载量更好地与HIV相关性痴呆（HAD）相关。早期对猴HIV/恒河猴NeuroAIDS模型的研究证实，患有脑炎的猕猴脑中的病理变化与血小板衍生生长因子（PDGF）和趋化因子CXCL 10的上调有关。由于巨噬细胞释放的炎症介质的复杂相互作用通常导致HAD中神经毒素的诱导，我们假设PDGF可以与IFN-γ相互作用以调节这些主要病毒靶细胞中CXCL 10的表达。尽管单独的PDGF对人巨噬细胞中CXCL 10的诱导没有影响，但与IFN-γ结合，其通过转录和转录后机制显著增强CXCL 10 RNA和蛋白的表达。信号分子，如JAK和STAT，PI 3 K，MAPK和NF-κ B被发现在CXCL 10的协同诱导中发挥作用。此外，PDGF通过激活p38 MAPK能够增加IFN-γ诱导的CXCL 10 mRNA的稳定性。了解CXCL 10协同上调的机制有助于HAD治疗方式的发展。
There is increasing cumulative evidence that activated mononuclear phagocytes (macrophages/microglia) releasing inflammatory mediators in the CNS are a better correlate of HIV-associated dementia (HAD) than the actual viral load in the brain. Earlier studies on simian HIV/rhesus macaque model of NeuroAIDS confirmed that pathological changes in brains of macaques with encephalitis were associated with up-regulation of platelet-derived growth factor (PDGF) and the chemokine, CXCL10. Because the complex interplay of inflammatory mediators released by macrophages often leads to the induction of neurotoxins in HAD, we hypothesized that PDGF could interact with IFN-gamma to modulate the expression of CXCL10 in these primary virus target cells. Although PDGF alone had no effect on the induction of CXCL10 in human macrophages, in conjunction with IFN-gamma, it significantly augmented the expression of CXCL10 RNA & protein through transcriptional and posttranscriptional mechanisms. Signaling molecules, such as JAK and STATs, PI3K, MAPK, and NF-kappa B were found to play a role in the synergistic induction of CXCL10. Furthermore, PDGF via its activation of p38 MAPK was able to increase the stability of IFN-gamma-induced CXCL10 mRNA. Understanding the mechanisms involved in the synergistic up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.