Dhillon Navneet Kaur, Peng Fuwang, Ransohoff Richard M, Buch Shilpa
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
J Immunol. 2007 Sep 1;179(5):2722-30. doi: 10.4049/jimmunol.179.5.2722.
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-kappaB 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.
越来越多的累积证据表明，在中枢神经系统中释放炎症介质的活化单核吞噬细胞（巨噬细胞/小胶质细胞）比大脑中的实际病毒载量更能体现与HIV相关痴呆（HAD）的关联。早期对猴免疫缺陷病毒/恒河猴神经艾滋病模型的研究证实，患有脑炎的猕猴大脑中的病理变化与血小板衍生生长因子（PDGF）和趋化因子CXCL10的上调有关。由于巨噬细胞释放的炎症介质之间复杂的相互作用通常会导致HAD中神经毒素的诱导，我们推测PDGF可能与γ干扰素相互作用，以调节这些主要病毒靶细胞中CXCLl0的表达。虽然单独的PDGF对人巨噬细胞中CXCL10的诱导没有影响，但与γ干扰素一起时，它通过转录和转录后机制显著增强了CXCL10 RNA和蛋白质的表达。发现信号分子，如JAK和STATs、PI3K、MAPK和NF-κB在CXCL10的协同诱导中起作用。此外，PDGF通过激活p38 MAPK能够增加γ干扰素诱导的CXCL10 mRNA的稳定性。了解CXCL10协同上调所涉及的机制可能有助于开发针对HAD的治疗方法。
