Chizzolini C, Rezzonico R, Ribbens C, Burger D, Wollheim F A, Dayer J M
University Hospital, Geneva, Switzerland.
Arthritis Rheum. 1998 Nov;41(11):2039-47. doi: 10.1002/1529-0131(199811)41:11<2039::AID-ART20>3.0.CO;2-1.
To assess the role of T lymphocyte-fibroblast contact in type I collagen production by cultured dermal fibroblasts from normal individuals and from patients with diffuse systemic sclerosis (SSc).
Cell membranes were prepared from activated CD4+ and CD8+ T cells, or type 1 T helper (Th1) clones, and added to confluent fibroblast monolayers. Type I collagen production was measured in culture supernatants, and messenger RNA (mRNA) levels of type I procollagen alpha1 (pro alpha1[I]) and matrix metalloproteinase 1 (MMP-1) were evaluated by Northern hybridization analysis.
Dose-dependent inhibition of type I collagen production was observed with CD4+ and CD8+ T cells from both SSc patients and controls. Inhibition of type I collagen was significantly less pronounced in fibroblasts from SSc patients than in fibroblasts from controls (P < 0.02). Inhibition was not reversed by the addition of exogenous transforming growth factor beta, interleukin-4, interleukin-1 receptor antagonist, anti-tumor necrosis factor, anti-CD40, or indomethacin, whereas anti-interferon-gamma (IFNgamma) reversed Th1-mediated inhibition. This inhibitory activity was specific for type I collagen, since mRNA levels of pro alpha1(I) were decreased, whereas mRNA levels of MMP-1 were strongly increased.
The production of type I collagen by skin fibroblasts is specifically down-regulated by membranes from activated T cells. The contact-dependent regulatory activity exerted by T cells on fibroblasts depends, at least in part, on the presence of membrane-associated IFNgamma. However, SSc fibroblasts are more resistant to inhibition than are fibroblasts from normal individuals.
评估T淋巴细胞与成纤维细胞接触在正常个体及弥漫性系统性硬化症（SSc）患者培养的真皮成纤维细胞产生I型胶原蛋白过程中的作用。
从活化的CD4⁺和CD8⁺T细胞或1型辅助性T细胞（Th1）克隆制备细胞膜，并添加到汇合的成纤维细胞单层中。测量培养上清液中I型胶原蛋白的产生，并通过Northern杂交分析评估I型前胶原α1（proα1[I]）和基质金属蛋白酶1（MMP-1）的信使核糖核酸（mRNA）水平。
观察到SSc患者和对照组的CD4⁺和CD8⁺T细胞对I型胶原蛋白产生有剂量依赖性抑制作用。SSc患者的成纤维细胞中I型胶原蛋白的抑制作用明显弱于对照组的成纤维细胞（P < 0.02）。添加外源性转化生长因子β、白细胞介素-4、白细胞介素-1受体拮抗剂、抗肿瘤坏死因子、抗CD40或吲哚美辛不能逆转这种抑制作用，而抗干扰素-γ（IFNγ）可逆转Th1介导的抑制作用。这种抑制活性对I型胶原蛋白具有特异性，因为proα1（I）的mRNA水平降低，而MMP-1的mRNA水平显著升高。
活化T细胞的细胞膜可特异性下调皮肤成纤维细胞I型胶原蛋白的产生。T细胞对成纤维细胞施加的接触依赖性调节活性至少部分取决于膜相关IFNγ的存在。然而，SSc成纤维细胞比正常个体的成纤维细胞对抑制作用更具抗性。
