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

我们先前已经证明，人单核细胞来源的巨噬细胞(MDM) 感染HIV-1并在没有外源性巨噬细胞的情况下维持 集落刺激因子(M-CSF)产生内源性M-CSF 比未感染的细胞高得多。的动力学和水平 M-CSF的产生与HIV-1的产生速度和数量是平行的。 相比之下，细胞因子TNF、IL-1、IL-6和GM-CSF的产生 在MDM体外感染过程中未观察到。提高产量 M-CSF的活性依赖于HIV-1在培养物中的活跃复制 系统。我们最近发现，治疗艾滋病毒感染的MDM 这种名为AZT的药物不仅能完全抑制HIV-1RT 活性，但也削减了M-CSF的产生，进一步支持 艾滋病毒在增强M-CSF产生中的直接作用。这表明 内源性M-CSF的产生有助于白血病的存活 HIV感染的单核细胞来源的巨噬细胞，使它们能够发挥作用 为病毒蓄水池，并便于病毒在体内传播。 确定潜在的细胞和分子机制的工作正在进行中 对这一现象负有责任，重点是通过具体的监管 HIV蛋白质。我们还在调查两者之间的相关性 白介素2、转化生长因子β、白介素4和白介素10等细胞因子对血管内皮细胞生长的影响 人巨噬细胞集落刺激因子的产生及其对HIV-1复制的影响 MDM。我们的结果可能最终导致新的治疗方法 旨在消除或控制HIV在人类体内的表达 单核/巨噬细胞(MO)，从而降低了 将病毒传播给更易受感染的CD4+T淋巴细胞。 由于艾滋病的特征是细胞因子的普遍失调 产生，我们已经暗示内皮素-1(ET-1)的参与。 在这种疾病中，我们还在研究ET-1基因的调节 参与免疫反应的各种细胞因子的表达。我们有 发现细胞因子干扰素-γ(干扰素-g)能够诱导 ET-1在人巨噬细胞中的表达呈浓度依赖性，但 与观察到的响应 诱导剂PMA，表明另一种细胞蛋白的诱导可能 在干扰素-g诱导ET-1之前。尽管我们抑制的能力 干扰素-g通过可溶性肿瘤坏死因子受体诱导ET-1的作用 对于肿瘤坏死因子，这种细胞因子不直接诱导ET-1的产生，但 干扰素-γ促进ET-1的产生。此外，增加的肿瘤坏死因子 未观察到干扰素-g基因的表达。我们目前正在检查 肿瘤坏死因子受体在这一反应中可能发挥的作用。到目前为止，我们的研究 提示肿瘤坏死因子受体是这一过程的关键介质，并提高 可溶性肿瘤坏死因子受体在肿瘤治疗中的应用 ET-1介导的病理状态。

We have previously shown that human monocyte-derived macrophages (MDM) infected with HIV-1 and maintained in the absence of exogenous macrophage colony stimulating factor (M-CSF) produce endogenous M-CSF at levels substantially higher than uninfected cells. The kinetics and level of M-CSF production paralleled both the rate and amount of HIV-1 produced. In contrast, production of the cytokines TNF, IL-1, IL-6 and GM- CSF was not observed during in vitro infection of the MDM. Enhanced production of M-CSF was dependent on active replication of HIV-1 within the culture system. We have recently found that treatment of HIV-infected MDM with the drug, AZT, not only leads to complete inhibition of HIV-1 RT activity, but also ablates the production of M-CSF, further supporting a direct role for HIV in enhanced M-CSF production. This suggests that endogenous production of M-CSF can contribute to the survival of HIV-infected monocyte-derived macrophages, enable them to function as a reservoir for the virus, and facilitate the spread of virus in vivo. Work is ongoing to determine potential cellular and molecular mechanisms responsible for this phenomenon, with emphasis on regulation by specific HIV proteins. We are also investigating the correlation between the effects of select cytokines, such as IL-2, TGF-beta, IL-4 and IL-10, on M-CSF production and the effects observed on HIV-1 replication in human MDM. Our results could ultimately lead to new therapeutic approaches directed at eliminating or controlling the expression of HIV in human monocytes/macrophages (MO), thereby reducing the possibility of transmission of virus to the more susceptible CD4+ T lymphocytes. Inasmuch as AIDS is characterized by a general dysregulation of cytokine production, and we have implicated the involvement of endothelin-1 (ET-1) in this disease, we are also investigating the regulation of ET-1 gene expression by various cytokines involved in immune responses. We have found that the cytokine, interferon-gamma (IFN-g) is capable of inducing expression of ET-1 in human MO in a concentration-dependent manner, but expression occurs late compared to that observed in response to the inducer, PMA, indicating that induction of another cellular protein may precede the induction of ET-1 by IFN-g. Although our ability to inhibit the induction of ET-1 by IFN-g by soluble TNF receptors suggested a role for TNF, this cytokine did not directly induce ET-1 production, but enhanced ET-1 production caused by IFN-g. In addition, increased TNF gene expression by IFN-g was not observed. We are currently examining the roles TNF receptors may play in this response. Thus far, our studies suggest that TNF receptors are key mediators of this process and raise the possibility of the therapeutic use of soluble TNF receptors in ET-1-mediated pathologic conditions.