Parry S L, Sebbag M, Feldmann M, Brennan F M
Kennedy Institute of Rheumatology, Sunley Division, Hammersmith, London, United Kingdom.
J Immunol. 1997 Apr 15;158(8):3673-81.
IL-10, originally described as a cytokine synthesis inhibitory factor, is secreted by a number of cells of the immune system, including monocytes and T cells. IL-10 is a potent inhibitor of monocyte/macrophage activation, and we have shown previously this cytokine to be a major endogenous down-regulator of TNF-alpha in the rheumatoid joint. The mechanisms involved in regulating IL-10 production by cells of the monocyte/macrophage lineage are not yet clear, and most studies to date have used an exogenous triggering signal such as LPS. In this study, we have investigated the effects of cell-cell contact between human peripheral blood-derived activated T cells and monocytes in regulating monocyte IL-10 production. T cells, prestimulated with anti-CD3 mAb or with phorbol 12,13 di-butyrate and ionomycin, were fixed with glutaraldehyde and then incubated with monocytes. Fixed prestimulated T cells induced monocytes to secrete both IL-10 and TNF-alpha, and in addition, enhanced LPS-stimulated monocyte production of IL-10 and TNF-alpha in a dose-dependent manner. Stimulation of monocyte IL-10 production was abrogated when T cells were separated physically from monocytes within the tissue culture well. Using neutralizing Abs, we show that T cell contact-mediated induction of monocyte IL-10 is partially dependent on endogenous TNF-alpha and IL-1. Furthermore, T cell membrane TNF-alpha was shown to be one of the contact-mediated signals regulating monocyte IL-10 production. Endogenous IL-10 was shown to down-regulate T cell contact-mediated monocyte TNF-alpha production. Collectively, our results demonstrate that an autoregulatory loop exists involving both secreted and membrane-associated forms of IL-10 and TNF-alpha, and suggest that T cell-monocyte cognate interaction may play an important role in the regulation of monocyte cytokine production.
白细胞介素-10最初被描述为一种细胞因子合成抑制因子，由包括单核细胞和T细胞在内的多种免疫系统细胞分泌。白细胞介素-10是单核细胞/巨噬细胞激活的强效抑制剂，我们之前已经证明这种细胞因子是类风湿关节中肿瘤坏死因子-α的主要内源性下调因子。单核细胞/巨噬细胞谱系细胞调节白细胞介素-10产生的机制尚不清楚，迄今为止大多数研究使用的是外源性触发信号，如脂多糖。在本研究中，我们研究了人外周血来源的活化T细胞与单核细胞之间的细胞间接触对调节单核细胞白细胞介素-10产生的影响。用抗CD3单克隆抗体或佛波醇12,13-二丁酸酯和离子霉素预刺激的T细胞，用戊二醛固定，然后与单核细胞一起孵育。固定的预刺激T细胞诱导单核细胞分泌白细胞介素-10和肿瘤坏死因子-α，此外，还以剂量依赖的方式增强脂多糖刺激的单核细胞白细胞介素-10和肿瘤坏死因子-α的产生。当在组织培养孔中将T细胞与单核细胞物理分离时，单核细胞白细胞介素-10的产生受到抑制。使用中和抗体，我们表明T细胞接触介导的单核细胞白细胞介素-10诱导部分依赖于内源性肿瘤坏死因子-α和白细胞介素-1。此外，T细胞膜肿瘤坏死因子-α被证明是调节单核细胞白细胞介素-10产生的接触介导信号之一。内源性白细胞介素-10被证明可下调T细胞接触介导的单核细胞肿瘤坏死因子-α的产生。总的来说，我们的结果表明存在一个涉及白细胞介素-10和肿瘤坏死因子-α的分泌形式和膜相关形式的自调节环，并表明T细胞-单核细胞同源相互作用可能在单核细胞细胞因子产生的调节中起重要作用。
