EFFECTS OF IFN-GAMMA AND IL-4 ON IL-1 PRODUCTION BY HUMAN MONOCYTES

IFN-γ 和 IL-4 对人单核细胞产生 IL-1 的影响

• 批准号: 3811204
• 负责人: R P DONNELLY
• 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/3811204
• 关键词: RNA; cytokine receptors; electrophoresis; human tissue; immunomodulators; immunoregulation; interferons; interleukin 1; interleukin 4; interleukin 6; leukocyte activation /transformation; nucleic acid hybridization; tumor necrosis factor alpha

In this project we investigated the effects of two distinct T cell-derived lymphokines, IFN-gamma and IL-4, on the ability of human monocytes to produce IL-1. IL-4 inhibits IL-1 production by highly purified normal human monocytes. We have found that Inhibition Is maximal or near maximal with IL-4 concentrations as low as ng/ml and most pronounced when IL-4 is added to monocyte cultures prior to or simultaneous with an IL-1 inducing stimulus such as LPS. Northern blot analyses revealed that IL-4 not only dramatically, reduced the steady-state message levels for IL-1 beta but also those of TNF alpha and IL-6. The inhibitory effect was not stimulus-specific because IL-4 suppressed IL-1 production Induced by three distinct monocyte activation stimuli: LPS, PMA and Staphylococcus aureus Cowan (SAC). Furthermore, monocytes expressed a relatively small number of high affinity IL-4 receptors (l50-300R per cell; Kd - 32 pill) indicating that relatively few receptors are necessary to generate the inhibitory, effect. Although both IFN-gamma and IL-4 upregulated MHC class II antigen (HLA-DR) expression by monocytes, they exhibited opposite effects on IL-1 production: IFN-gamma significantly enhanced IL-1 production induced by submaximal concentrations of LPS; whereas, IL-4 suppressed IL-1 production. Moreover, IL-4 largely neutralized the potentiating effect of IFN-gamma suggesting that IL-4 may be an effective antagonist of certain IFN-gamma-- inducible effects. These findings demonstrate that the relative levels of IFN-gamma and IL-4 may profoundly influence the expression of IL-1, a property that may be important in the control of monocyte/macrophage activation at specific tissue sites. These findings also suggest that IL-4 might have clinical utility as an antiinflammatory agent in the treatment of diseases such as rheumatoid arthritis where overexpression of the monokines IL-1, TNF alpha and IL-6 has been observed.

在这个项目中，我们研究了两种不同的T细胞来源的 淋巴因子IFN-γ和IL-4对人单核细胞 产生IL-1。IL-4抑制正常人IL-1的产生 单核细胞我们已经发现，抑制是最大或接近最大的， IL-4浓度低至ng/ml，当加入IL-4时最明显 在IL-1诱导之前或同时， 刺激物如LPS。北方印迹分析显示IL-4不仅 显著降低了IL-1 β的稳态信息水平， 也包括TNF α和IL-6。抑制作用不是 刺激特异性，因为IL-4抑制IL-1的产生 不同的单核细胞活化刺激：LPS、PMA和金黄色葡萄球菌 科万（SAC）。此外，单核细胞表达相对少量的 高亲和力IL-4受体（150 - 300 R/细胞; Kd - 32 pill）表明 相对较少的受体是产生抑制所必需的， 效果虽然IFN-γ和IL-4均上调MHC II类抗原 （HLA-DR）表达的单核细胞，他们表现出相反的影响IL-1 产生：IFN-γ显著增强由IFN-γ诱导的IL-1产生。 次最大浓度的LPS;而IL-4抑制IL-1的产生。 此外，IL-4在很大程度上中和了IFN-γ的增强作用， 提示IL-4可能是某些IFN-γ的有效拮抗剂， 诱导效应这些发现表明， IFN-γ和IL-4可能深刻地影响IL-1的表达， 在控制单核细胞/巨噬细胞中可能很重要的性质 在特定组织部位激活。这些发现还表明，IL-4 可能具有作为治疗中的抗肿瘤剂的临床效用 类风湿性关节炎等疾病中， 已经观察到单核因子IL-1、TNF α和IL-6。