Punnonen J, de Waal Malefyt R, van Vlasselaer P, Gauchat J F, de Vries J E
DNAX Research Institute of Molecular and Cellular Biology, Human Immunology Department, Palo Alto, CA 94304-1104.
J Immunol. 1993 Aug 1;151(3):1280-9.
In the present study it is demonstrated that IL-10 and viral (v)-IL-10 inhibit IL-4-induced IgG4 and IgE synthesis in cultures of PBMC from healthy nonatopic donors. The inhibition occurred at the mRNA level. IL-10 strongly reduced IL-4-induced expression of both germline and productive epsilon transcripts in PBMC. The inhibitory effects were completely neutralized, or IgG4 and IgE synthesis was even enhanced, by anti-IL-10 mAb, demonstrating the specificity of the reaction. IL-4-induced IgG4 and IgE synthesis by PBMC was monocyte dependent. IL-4 failed to induce IgG4 or IgE synthesis by monocyte-depleted PBMC, but the production of these isotypes was completely restored by reconstitution with autologous monocytes. However, monocytes preincubated with IL-10 for 24 h failed to provide the accessory signals required for IL-4-induced IgG4 and IgE synthesis, indicating that the inhibitory effects of IL-10 are indirectly mediated via monocytes. This notion was further supported by the finding that IL-10 and v-IL-10 failed to inhibit IL-4-induced IgE synthesis in the absence of monocytes, i.e., when highly purified B cells were cultured in the presence of anti-CD40 mAb or cloned activated CD4+ T cells. Moreover, IL-10 failed to inhibit IL-4-induced germline epsilon mRNA synthesis in highly purified B cells. The inhibitory effects of IL-10 could not be restored by exogenous TNF-alpha or IL-6, indicating that the inhibitory effects were not mediated through inhibition of production of these cytokines. This is compatible with the observation that monocytes preincubated with IL-10 did not inhibit IgG4 or IgE synthesis in a monocyte- and T cell-independent culture system, in which purified B cells were cultured in the presence of anti-CD40 mAb and IL-4. Collectively, these data indicate that IL-10 mediates a potent, monocyte-dependent, inhibitory effect on IL-4-induced IgG4 and IgE production by human PBMC.
在本研究中，已证明白细胞介素-10（IL-10）和病毒（v）-IL-10可抑制来自健康非特应性供体的外周血单个核细胞（PBMC）培养物中IL-4诱导的IgG4和IgE合成。这种抑制作用发生在mRNA水平。IL-10强烈降低了PBMC中IL-4诱导的种系和有功能的ε转录本的表达。抗IL-10单克隆抗体完全中和了这种抑制作用，甚至增强了IgG4和IgE的合成，证明了该反应的特异性。PBMC中IL-4诱导的IgG4和IgE合成是单核细胞依赖性的。IL-4不能诱导去除单核细胞的PBMC合成IgG4或IgE，但通过用自体单核细胞重建可完全恢复这些同种型的产生。然而，用IL-10预孵育24小时的单核细胞未能提供IL-4诱导的IgG4和IgE合成所需的辅助信号，表明IL-10的抑制作用是通过单核细胞间接介导的。这一观点进一步得到以下发现的支持：在没有单核细胞的情况下，即当在抗CD40单克隆抗体或克隆活化的CD4 + T细胞存在下培养高度纯化的B细胞时，IL-10和v-IL-10不能抑制IL-4诱导的IgE合成。此外，IL-10不能抑制高度纯化的B细胞中IL-4诱导的种系ε mRNA合成。外源性肿瘤坏死因子-α（TNF-α）或白细胞介素-6（IL-6）不能恢复IL-10的抑制作用，表明抑制作用不是通过抑制这些细胞因子的产生介导的。这与以下观察结果一致：在单核细胞和T细胞非依赖性培养系统中，用IL-10预孵育的单核细胞不抑制IgG4或IgE合成，在该系统中，纯化的B细胞在抗CD40单克隆抗体和IL-4存在下培养。总体而言，这些数据表明IL-10对人PBMC中IL-4诱导的IgG4和IgE产生介导了一种强大的、单核细胞依赖性的抑制作用。
