Donnelly R P, Fenton M J, Finbloom D S, Gerrard T L
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
J Immunol. 1990 Jul 15;145(2):569-75.
We have demonstrated that IL-4 markedly inhibits IL-1 production by highly purified normal human monocytes. When added to monocyte cultures, IL-4 suppressed LPS-induced IL-1 production in a time- and dose-dependent manner. Concentrations of IL-4 as low as 100 pg/ml reduced IL-1 production by approximately 50%, and doses of 1 ng/ml or higher suppressed IL-1 production by more than 90%. Maximal inhibition required that IL-4 be added before or simultaneous with LPS. Northern dot blot analyses revealed that IL-4 not only dramatically reduced the steady-state IL-1 beta mRNA levels in LPS-stimulated monocytes, 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 a variety of monocyte activation stimuli, including LPS, PMA, and Staphylococcus aureus Cowan strain. Monocytes expressed a relatively small number of high affinity IL-4R (approximately 150/cell; Ka = 3.15 +/- 1.13 x 10(10) M-1) indicating that relatively few receptors are necessary to generate the inhibitory effect. IL-4 enhanced monocyte MHC class II Ag (HLA-DR) expression in a manner similar to that of IFN-gamma. However, although both IFN-gamma and IL-4 up-regulated HLA-DR expression, they exhibited opposite effects on IL-1 production: IFN-gamma significantly enhanced monocyte 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-induced effects. Together these findings demonstrate that the relative levels of IFN-gamma and IL-4 may profoundly influence the state of monocyte activation by differentially regulating the expression of IL-1.
我们已经证明，白细胞介素-4（IL-4）可显著抑制高度纯化的正常人单核细胞产生白细胞介素-1（IL-1）。将IL-4添加到单核细胞培养物中时，它能以时间和剂量依赖的方式抑制脂多糖（LPS）诱导的IL-1产生。低至100 pg/ml的IL-4浓度可使IL-1产生减少约50%，1 ng/ml或更高剂量可使IL-1产生抑制超过90%。最大抑制作用要求在LPS之前或同时添加IL-4。Northern斑点印迹分析显示，IL-4不仅显著降低LPS刺激的单核细胞中稳态IL-1β mRNA水平，还降低肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的水平。这种抑制作用并非刺激特异性的，因为IL-4可抑制多种单核细胞激活刺激物诱导的IL-1产生，包括LPS、佛波酯（PMA）和金黄色葡萄球菌考恩株。单核细胞表达相对少量的高亲和力IL-4受体（约150个/细胞；Ka = 3.15 +/- 1.13 x 10(10) M-1），表明产生抑制作用所需的受体相对较少。IL-4以类似于干扰素-γ（IFN-γ）的方式增强单核细胞MHC II类抗原（HLA-DR）的表达。然而，尽管IFN-γ和IL-4均上调HLA-DR表达，但它们对IL-1产生表现出相反的作用：IFN-γ显著增强亚最大浓度LPS诱导的单核细胞IL-1产生；而IL-4则抑制IL-1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诱导效应的有效拮抗剂。这些发现共同表明，IFN-γ和IL-4的相对水平可能通过差异调节IL-1的表达而深刻影响单核细胞的激活状态。
