Sebbag M, Parry S L, Brennan F M, Feldmann M
Kennedy Institute of Rheumatology, London, GB.
Eur J Immunol. 1997 Mar;27(3):624-32. doi: 10.1002/eji.1830270308.
Previous studies in the laboratory have shown that the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The mechanisms involved in regulating monocyte/macrophage cytokine production are not yet fully understood, but are thought to involve both soluble factors and cell/cell contact with other cell types. We and others have previously demonstrated that T cells activated through the T cell receptor/CD3 complex induce monocyte TNF-alpha production by contact-mediated signals. In this report, we investigated further whether T cells activated by cytokines in the absence of T cell receptor stimulation also regulate monocyte cytokine production. T cells were activated in an antigen-independent manner using the cytokines interleukin (IL)-15 or IL-2 alone, or in combination with IL-6 and TNF-alpha. Subsequently, T cells were fixed and incubated with monocytes. Fixed, cytokine-stimulated T cells induced monocytes to secrete TNF-alpha in a dose-dependent manner, but did not induce secretion of IL-10, a potent endogenous down-regulator of TNF-alpha and other pro-inflammatory cytokines. Stimulation of monocyte TNF-alpha was markedly inhibited when T cells were physically separated from monocytes within the tissue culture well, confirming that T cell contact is necessary. T cell acquisition of monocyte-activating capacity was shown to be dependent on the period of cytokine stimulation, with T cells activated for 8 days more effective than T cells activated for shorter periods. Addition of interferon-gamma or granulocyte/macrophage colony-stimulating factor to the T cell/monocyte cultures enhanced T cell induction of monocyte TNF-alpha by threefold and ninefold, respectively. The results from this model of cognate interaction suggest that cytokine-stimulated T cells, interacting with macrophages in the rheumatoid synovial membrane, may contribute to the continuous excessive production of TNF-alpha observed in the RA joint, and to the imbalance of pro-inflammatory cytokines over anti-inflammatory cytokines.
此前在实验室进行的研究表明，促炎细胞因子肿瘤坏死因子（TNF）-α在类风湿关节炎（RA）的发病机制中起关键作用。调节单核细胞/巨噬细胞细胞因子产生的机制尚未完全明确，但一般认为其涉及可溶性因子以及细胞与其他细胞类型之间的细胞/细胞接触。我们和其他研究人员之前已证明，通过T细胞受体/CD3复合物激活的T细胞可通过接触介导的信号诱导单核细胞产生TNF-α。在本报告中，我们进一步研究了在不存在T细胞受体刺激的情况下，由细胞因子激活的T细胞是否也能调节单核细胞细胞因子的产生。单独使用细胞因子白细胞介素（IL）-15或IL-2，或与IL-6和TNF-α联合使用，以抗原非依赖性方式激活T细胞。随后，将T细胞固定并与单核细胞共同孵育。经细胞因子刺激的固定T细胞以剂量依赖性方式诱导单核细胞分泌TNF-α，但未诱导IL-10的分泌，IL-10是TNF-α和其他促炎细胞因子的一种有效的内源性下调因子。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TNF-α的刺激受到显著抑制，这证实了T细胞接触是必需的。T细胞获得单核细胞激活能力被证明取决于细胞因子刺激的时间，激活8天的T细胞比激活较短时间的T细胞更有效。向T细胞/单核细胞培养物中添加干扰素-γ或粒细胞/巨噬细胞集落刺激因子，可分别使T细胞诱导单核细胞TNF-α的能力增强3倍和9倍。这种同源相互作用模型的结果表明，在类风湿滑膜中与巨噬细胞相互作用的细胞因子刺激的T细胞，可能导致在RA关节中观察到的TNF-α持续过量产生，以及促炎细胞因子与抗炎细胞因子之间的失衡。
