Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor α
Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor α
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DOI：
10.1002/art.11129
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
Dayer, JM
中科院分区：
文献类型：
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作者：
Chizzolini, C;Parel, Y;Dayer, JM
客观的。在系统性硬化症（SSc；硬皮病）中，T 细胞浸润正在经历纤维化变化的器官，并可能参与成纤维细胞胶原蛋白生产的失调。本研究的目的是从功能上表征早期 SSc 中浸润皮肤病变的 T 细胞，并研究其影响真皮成纤维细胞产生 I 型胶原和间质胶原酶（基质金属蛋白酶 1 [MMP-1]）的能力。方法。使用四色细胞分析来表征 SSc 患者皮肤产生的 T 细胞系中干扰素 γ (IFNgamma) 和白细胞介素 4 (IL-4) 的子集分布和产生。生成了 T 细胞克隆，并评估了它们调节 SSc 患者和正常个体的成纤维细胞产生胶原蛋白和 MMP-1 的能力。中和试剂用于鉴定参与成纤维细胞调节的 T 细胞介质。结果。早期 SSc 个体的皮肤含有优先产生高水平 IL-4 的 T 细胞。克隆的 CD4+ Th2 样细胞抑制正常成纤维细胞产生胶原蛋白。 Th2 细胞依赖性抑制至少部分是接触依赖性的，基本上由肿瘤坏死因子 α (TNFα) 介导，并且比促纤维化 IL-4 和转化生长因子 β 细胞因子诱导的增强占主导地位。 MMP-1 产生的同时诱导证实了这些观察结果的特异性。为了发挥抑制作用，Th2 细胞需要通过 CD3 连接来激活。 Th2细胞通过细胞间相互作用抑制正常成纤维细胞产生胶原蛋白的能力比Th1细胞弱，并且SSc成纤维细胞对抑制具有抵抗力。结论。这些发现表明，尽管Th2细胞产生IL-4，但由于TNFα的主导作用，Th2细胞仍减少真皮成纤维细胞合成I型胶原，并表明基于TNFα阻断的旨在控制SSc纤维化的策略可能是不明智的。
Objective. In systemic sclerosis (SSc; scleroderma), T cells infiltrate organs undergoing fibrotic changes and may participate in dysregulated production of collagen by fibroblasts. The objective of this study was to functionally characterize T cells infiltrating skin lesions in early SSc and investigate their capacity to affect production of type I collagen and interstitial collagenase (matrix metalloproteinase 1 [MMP-1]) by dermal fibroblasts.Methods. Four-color cytometric analysis was used to characterize subset distribution and production of interferon-gamma (IFNgamma) and interleukin-4 (IL-4) in T cell lines generated from the skin of patients with SSc. T cell clones were generated, and their capacity to modulate collagen and MMP-1 production by fibroblasts derived from patients with SSc and from normal individuals was assessed. Neutralizing reagents were used to identify T cell mediators involved in fibroblast modulation.Results. The skin of individuals with early-stage SSc contained T cells preferentially producing high levels of IL-4. Cloned CD4+ Th2-like cells inhibited collagen production by normal fibroblasts. Th2 cell-dependent inhibition was, at least in part, contact-dependent, was essentially mediated by tumor necrosis factor alpha (TNFalpha), and was dominant over the enhancement induced by profibrotic IL-4 and transforming growth factor beta cytokines. The simultaneous induction of MMP-1 production confirmed the specificity of these observations. To be inhibitory, Th2 cells required activation by CD3 ligation. Th2 cells were less potent than were Th1 cells in inhibiting collagen production by normal fibroblasts via cell-to-cell interaction, and SSc fibroblasts were resistant to inhibition.Conclusion. These findings indicate that, despite their production of IL-4, Th2 cells reduce type I collagen synthesis by dermal fibroblasts because of the dominant effect of TNFalpha, and suggest that strategies based on TNFalpha blockade aimed at controlling fibrosis in SSc may be unwise.