REGULATION OF M-CSF AND ET-1 PRODUCTION IN HUMAN MONOCYTES

人单核细胞中 M-CSF 和 ET-1 产生的调节

• 批准号: 6101219
• 负责人: K. A CLOUSE-STREBEL
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6101219
• 关键词: colony stimulating factor; cytokine; cytokine receptors; endothelin; gene induction /repression; human immunodeficiency virus 1; human tissue; interferon gamma; interleukin 1; interleukin 4; interleukin 6; macrophage; monocyte; tumor necrosis factor alpha; tumor necrosis factor beta; virus protein; virus replication

We previously showed that monocyte-derived macrophages (MDM) infected with HIV-1 produce high levels of macrophage colony stimulating factor (M-CSF). M-CSF production paralleled both the rate and amount of HIV-1 produced and enhanced production of M-CSF was dependent on active replication of HIV-1. This was supported by our finding that treatment of HIV- infected MDM with AZT leads to complete inhibition of HIV-1 RT activity, and also ablates the production of M-CSF. The lymphokine, interleukin-2 (IL-2), reportedly upregulates M-CSF receptor expression and enhances M-CSF production by human monocytes, which increase the susceptibility of MDM to HIV-1 infection. IL-2 has been successfully used for therapeutic restoration of CD4+ T cells in AIDS patients, but its use is accompanied by a transient burst of HIV-1 RNA from unidentified cells. We investigated the ability of IL-2 to enhance HIV-1 expression in MDM by upregulating M-CSF production. Intriguingly, we found that exposure of MDM to IL-2 prior to infection leads to a dramatic decrease in HIV-1 replication, which correlates with an IL-2-induced down-modulation of the HIV-1 receptors CD4, CCR5 and CCR3. However, M-CSF production was not modulated (AIDS Fast Track 1998, 12:F59-F64).
Other studies looking at the effects of interleukin 15 (IL-15), which has similar biological activities and shares a common receptor gamma chain, show that IL-15 has no effect on HIV-1 replication when added prior to infection, but inhibits replication when added post infection. IL-15 does not modulate HIV receptor expression and it can stimulate production of M-CSF, suggesting that IL-2 and IL-15 have unique effects on MDM. Our results could lead to new therapeutic approaches directed at eliminating expression of HIV in human MDM, thereby reducing the possibility of transmission of virus to the more susceptible CD4+ T lymphocytes. Although M-CSF can modulate the susceptibility and rate of infection of MDM with HIV-1 and its production is enhanced following infection, its role in the infection of MDM with other viruses has not been characterized. We infected MDM with a panel of single stranded RNA viruses including HIV-1, HIV-2, measles virus (MV) and respiratory syncitial virus (RSV). We found that infection of MDM with monocytropic strains of HIV-2 also leads to enhanced production of M-CSF. However, infection of MDM with MV or RSV does not induce endogenous production of M-CSF. Specific production of M-CSF in response to HIV infection provides an example of how the virus uses a host derived protein to promote its survival and suggests that M-CSF antagonists may play an important role in the treatment of HIV disease.

我们以前的研究表明，单核细胞衍生的巨噬细胞（MDM）感染 与HIV-1产生高水平的巨噬细胞集落刺激因子 （M-CSF）。 M-CSF的产生与HIV-1的速度和数量有关 M-CSF的产生和增强的产生依赖于活性 HIV-1的复制。 我们的研究结果支持了这一点， 艾滋病病毒感染的MDM与AZT导致完全抑制HIV-1逆转录酶 活性，并且还消除M-CSF的产生。 淋巴因子， 据报道，白细胞介素-2（IL-2）上调M-CSF受体表达 并增强人单核细胞的M-CSF产生，这增加了 MDM对HIV-1感染的易感性。 IL-2已成功 用于治疗性恢复艾滋病患者的CD 4 + T细胞，但 它的使用伴随着HIV-1 RNA的短暂爆发， 不明细胞 我们研究了IL-2增强HIV-1的能力， 通过上调M-CSF产生在MDM中表达。 有趣的是，我们 发现MDM在感染前暴露于IL-2会导致显著的 HIV-1复制减少，这与IL-2诱导的 下调HIV-1受体CD 4、CCR 5和CCR 3。 然而，在这方面， M-CSF的产生不受调节（AIDS Fast Track 1998， 12：F59-F64）。
其他研究观察白细胞介素15的作用 IL-15具有相似的生物学活性， 受体γ链，表明IL-15对HIV-1复制没有影响 当在感染前添加时，但当在感染后添加时抑制复制 感染IL-15不调节HIV受体表达， 刺激M-CSF产生，表明IL-2和IL-15具有独特的 对MDM的影响我们的研究结果可能会导致新的治疗方法 旨在消除人类MDM中HIV的表达，从而减少 病毒传播给更易感的CD 4 + T细胞的可能性 淋巴细胞 虽然M-CSF可以调节感染的易感性和感染率， MDM与HIV-1和它的生产是增强感染后，其 在其他病毒感染MDM中的作用尚未被证实。 表征了我们用一组单链RNA感染MDM 病毒，包括HIV-1、HIV-2、麻疹病毒（MV）和呼吸道感染 合胞病毒（RSV）。我们发现，单细胞型糖尿病感染 HIV-2菌株也导致M-CSF的产生增强。然而，在这方面， 用MV或RSV感染MDM不诱导内源性 M-CSF M-CSF对HIV感染应答的特异性产生 提供了一个病毒如何使用宿主衍生蛋白质的例子， 促进其存活，并表明M-CSF拮抗剂可能发挥作用， 在艾滋病治疗中发挥重要作用。