Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: Possible relevance to pathophysiology of rheumatoid arthritis
Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: Possible relevance to pathophysiology of rheumatoid arthritis
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DOI：
10.1002/eji.1830270308
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发表时间：
1997-03-01
影响因子：
5.4
通讯作者：
Feldmann, M
中科院分区：
文献类型：
--
作者：
Sebbag, M;Parry, SL;Feldmann, M
实验室先前的研究表明，促炎细胞因子肿瘤坏死因子（TNF）-α在类风湿关节炎（RA）的发病机制中起着关键作用。参与调节单核细胞/巨噬细胞细胞因子产生的机制尚未完全了解，但被认为涉及可溶性因子和细胞/细胞与其他细胞类型的接触。我们和其他人以前已经证明，通过T细胞受体/CD 3复合物激活的T细胞通过接触介导的信号诱导单核细胞TNF-α的产生。在这份报告中，我们进一步研究了在T细胞受体刺激的情况下，细胞因子激活的T细胞是否也调节单核细胞细胞因子的产生。使用细胞因子白细胞介素（IL）-15或IL-2单独或与IL-6和TNF-α组合以抗原非依赖性方式活化T细胞。随后，将T细胞固定并与单核细胞一起孵育。固定的、马槟榔碱刺激的T细胞诱导单核细胞以剂量依赖性方式分泌TNF-α，但不诱导IL-10的分泌，IL-10是TNF-α和其他促炎细胞因子的有效内源性下调因子。当T细胞与组织培养孔内的单核细胞物理分离时，单核细胞TNF-α的刺激被显著抑制，证实T细胞接触是必要的。单核细胞活化能力的T细胞获得被证明是依赖于细胞因子刺激的时间，与T细胞激活8天比T细胞激活更短的时间内更有效。向T细胞/单核细胞培养物中加入干扰素-γ或粒细胞/巨噬细胞集落刺激因子分别增强T细胞对单核细胞TNF-α的诱导3倍和9倍。来自这种同源相互作用模型的结果表明，与类风湿性滑膜中的巨噬细胞相互作用的马槟榔碱刺激的T细胞可能有助于在RA关节中观察到的TNF-α的持续过量产生，以及促炎细胞因子相对于抗炎细胞因子的不平衡。
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.