Denton C P, Shi-Wen X, Sutton A, Abraham D J, Black C M, Pearson J D
Vascular Biology Research Centre, King's College London, Academic Unit of Rheumatology, Royal Free Hospital, UK.
Clin Exp Immunol. 1998 Nov;114(2):293-300. doi: 10.1046/j.1365-2249.1998.00721.x.
Perivascular infiltrates of inflammatory cells are a hallmark of lesional skin in scleroderma. We have explored the potential for scleroderma fibroblasts to modulate mononuclear leucocyte migration across endothelial cell monolayers in tissue culture, and to regulate expression of endothelial cell adhesion molecules. Fibroblasts were grown from skin biopsies of eight patients with active diffuse cutaneous scleroderma and from four healthy controls. Co-culture and conditioned medium transfer experiments examined the effect of soluble fibroblast products on mononuclear leucocyte (U937) cell migration across endothelial cell (1E-7) monolayers grown on tissue culture inserts. Co-culture of scleroderma, but not control fibroblasts, promoted transendothelial migration of U937 cells. Scleroderma fibroblast-conditioned medium had qualitatively similar effects and equivalent results were obtained using Jurkat-6 (T lymphocyte) cells, and with peripheral blood mononuclear cells from a patient with diffuse cutaneous scleroderma. Promotion of leucocyte migration does not appear to result from increased endothelial adhesion molecule expression, since fibroblast-conditioned medium did not up-regulate endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) or E-selectin. Moreover, leucocyte migration across cytokine-activated endothelial cell layers in co-culture with fibroblasts was less than across resting cells, although the selective effect of scleroderma fibroblast co-culture persisted. Recombinant monocyte chemoattractant protein-1 (MCP-1) or IL-8 increased passage of mononuclear leucocytes across endothelial cell monolayers, whilst anti-MCP-1, but not anti-IL-8 antibodies, significantly reduced the effect of fibroblast conditioned medium. These data suggest that systemic sclerosis (SSc) fibroblasts promote leucocyte migration across endothelial cell monolayers in tissue culture via an MCP-1-dependent mechanism. These findings may be relevant to the perivascular mononuclear leucocyte infiltrates characteristic of early SSc lesions.
炎症细胞的血管周围浸润是硬皮病皮损的一个标志。我们探讨了硬皮病成纤维细胞在组织培养中调节单核白细胞跨内皮细胞单层迁移以及调节内皮细胞黏附分子表达的潜力。从8例活动性弥漫性皮肤硬皮病患者的皮肤活检组织和4例健康对照者中培养成纤维细胞。共培养和条件培养基转移实验检测了可溶性成纤维细胞产物对单核白细胞（U937）跨组织培养插入物上生长的内皮细胞（1E - 7）单层迁移的影响。硬皮病成纤维细胞（而非对照成纤维细胞）的共培养促进了U937细胞的跨内皮迁移。硬皮病成纤维细胞条件培养基有定性相似的作用，使用Jurkat - 6（T淋巴细胞）细胞以及来自一名弥漫性皮肤硬皮病患者的外周血单核细胞也获得了相同结果。白细胞迁移的促进似乎并非源于内皮黏附分子表达增加，因为成纤维细胞条件培养基并未上调内皮细胞细胞间黏附分子 - 1（ICAM - 1）、血管细胞黏附分子 - 1（VCAM - 1）或E - 选择素的表达。此外，与成纤维细胞共培养时，白细胞跨细胞因子激活的内皮细胞层的迁移少于跨静息细胞的迁移，尽管硬皮病成纤维细胞共培养的选择性作用仍然存在。重组单核细胞趋化蛋白 - 1（MCP - 1）或白细胞介素 - 8增加了单核白细胞跨内皮细胞单层的通过，而抗MCP - 1抗体（而非抗白细胞介素 - 8抗体）显著降低了成纤维细胞条件培养基的作用。这些数据表明，系统性硬化症（SSc）成纤维细胞通过一种依赖MCP - 1的机制促进组织培养中白细胞跨内皮细胞单层迁移。这些发现可能与早期SSc病变特征性的血管周围单核白细胞浸润有关。
