Wong H L, Lotze M T, Wahl L M, Wahl S M
Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
J Immunol. 1992 Apr 1;148(7):2118-25.
As a multifunctional cytokine that can augment certain T cell responses, IL-4 is being evaluated currently as a possible therapeutic agent in the treatment of cancer patients. In this report, PBMC were isolated from such patients before and after IL-4 therapy and were analyzed for phenotypic and functional alterations. Differential blood counts showed that the relative percentages of lymphocytes and, to a lesser degree, monocytes decreased after treatment with IL-4. However, when phenotypically analyzed by FACS, monocyte numbers generally increased, whereas there was a decrease in lymphocyte numbers. Monocytes taken from patients before therapy and cultured with and without LPS exhibited normal patterns of monokine-specific (IL-1 beta and TNF-alpha) mRNA expression, as well as secretion of peptide. The addition of rIL-4 to these cultures, however, resulted in the down-regulation of both gene expression and peptide release. Although monocytes taken from post-therapy patients also displayed normal patterns of monokine gene expression and cytokine release after stimulation with LPS, they were no longer inhibited by the addition of exogenous rIL-4 in vitro. These data suggest that monocytes become refractory to the inhibitory effects of IL-4 after in vivo exposure to this cytokine. However, when these monocytes were examined for expression of CD14, CD32, and CD64, exogenous IL-4 was observed to decrease markedly the appearance of these markers, regardless of whether the cells were obtained before or after therapy. Furthermore, monocytes from post-therapy patients exhibited reduced production of PGE2 and superoxide anion, compared with cells obtained before therapy. This effect persisted in culture independent of the further addition of exogenous IL-4. These data suggest a dichotomy between the IL-4-dependent mechanisms that regulate monokine production and those that regulate certain other monocyte functions. The exact mechanisms that govern these two pathways are not known. These results have important clinical implications for the use of IL-4 as an immunotherapeutic agent, as well as providing insight into the physiologic role of IL-4.
作为一种能够增强某些T细胞反应的多功能细胞因子，白细胞介素-4（IL-4）目前正作为一种可能的治疗药物用于癌症患者的治疗评估。在本报告中，从接受IL-4治疗前后的此类患者中分离出外周血单核细胞（PBMC），并对其表型和功能改变进行分析。血细胞分类计数显示，用IL-4治疗后淋巴细胞的相对百分比下降，单核细胞的相对百分比在较小程度上也下降。然而，当通过荧光激活细胞分选术（FACS）进行表型分析时，单核细胞数量通常增加，而淋巴细胞数量减少。取自治疗前患者的单核细胞在有或无脂多糖（LPS）的情况下培养，均表现出正常的单核因子特异性（IL-1β和TNF-α）mRNA表达模式以及肽分泌。然而，向这些培养物中添加重组IL-4（rIL-4）会导致基因表达和肽释放的下调。尽管取自治疗后患者的单核细胞在用LPS刺激后也表现出正常的单核因子基因表达和细胞因子释放模式，但在体外添加外源性rIL-4后它们不再受到抑制。这些数据表明，单核细胞在体内接触这种细胞因子后对IL-4的抑制作用变得不敏感。然而，当检测这些单核细胞的CD14、CD32和CD64表达时，发现外源性IL-4能显著降低这些标志物的出现，无论细胞是在治疗前还是治疗后获得。此外，与治疗前获得的细胞相比，治疗后患者的单核细胞产生的前列腺素E2（PGE2）和超氧阴离子减少。这种效应在培养中持续存在，与是否进一步添加外源性IL-4无关。这些数据表明，调节单核因子产生的IL-4依赖性机制与调节某些其他单核细胞功能的机制之间存在二分法。控制这两条途径的确切机制尚不清楚。这些结果对于将IL-4用作免疫治疗药物具有重要的临床意义，同时也有助于深入了解IL-4的生理作用。
