Wong H L, Costa G L, Lotze M T, Wahl S M
Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
J Exp Med. 1993 Mar 1;177(3):775-81. doi: 10.1084/jem.177.3.775.
Interleukin (IL) 4 is a multifunctional T cell-derived cytokine that inhibits cytokine production and certain effector functions in human monocytes, while enhancing others. We show that IL-4 may contribute to the downregulation and resolution of an inflammatory response by selectively promoting expression of the IL-1 receptor antagonist (IL-1ra) that blocks the action of IL-1. IL-1ra specifically binds to the IL-1 receptor without initiating signal transduction. Peripheral blood monocytes obtained from cancer patients, before and immediately after a regimen of IL-4 immunotherapy, were examined for IL-1ra gene expression. After IL-4 therapy, monocytes from the patients showed a marked increase in IL-1ra mRNA. This selective induction of IL-1ra mRNA in circulating monocytes was reflected by significantly enhanced serum levels of IL-1ra (p < 0.01) during IL-4 therapy, which declined after IL-4 treatment. In vitro analysis of IL-4 regulation of monocytes from normal individuals revealed a dose-dependent induction of IL-1ra mRNA within 2-4 h after stimulation without a concomitant effect on the expression of IL-1 mRNA. Increased IL-1ra mRNA was not due to RNA stabilization, but occurred at the level of transcription. In the presence of LPS, IL-4 not only augmented IL-1ra levels, but markedly inhibited LPS-induced IL-1 mRNA expression. The selective upregulation of IL-1ra by resting or activated monocytes, coupled with inhibition of IL-1 production by activated monocytes, as we demonstrate both in vitro and in vivo, suggests that IL-4 may prove clinically useful as a systemic antiinflammatory agent.
白细胞介素（IL）-4是一种多功能的T细胞衍生细胞因子，它可抑制人单核细胞中的细胞因子产生和某些效应功能，同时增强其他功能。我们发现，IL-4可能通过选择性促进阻断IL-1作用的IL-1受体拮抗剂（IL-1ra）的表达，从而有助于炎症反应的下调和消退。IL-1ra特异性结合IL-1受体但不启动信号转导。检测了癌症患者在接受IL-4免疫治疗方案之前和之后立即获得的外周血单核细胞的IL-1ra基因表达。IL-4治疗后，患者的单核细胞显示IL-1ra mRNA显著增加。循环单核细胞中IL-1ra mRNA的这种选择性诱导反映在IL-4治疗期间血清IL-1ra水平显著升高（p < 0.01），而在IL-4治疗后下降。对正常个体单核细胞的IL-4调节进行的体外分析显示，刺激后2 - 4小时内IL-1ra mRNA呈剂量依赖性诱导，而对IL-1 mRNA的表达没有伴随影响。IL-1ra mRNA的增加不是由于RNA稳定，而是发生在转录水平。在脂多糖（LPS）存在的情况下，IL-4不仅增加IL-1ra水平，而且显著抑制LPS诱导的IL-1 mRNA表达。如我们在体外和体内所证明的，静息或活化的单核细胞对IL-1ra的选择性上调，以及活化单核细胞对IL-1产生的抑制，表明IL-4可能在临床上作为一种全身性抗炎剂有用。
