Adhesion molecule expression on skin endothelia in atopic dermatitis:: Effects of TNF-α and IL-4
Adhesion molecule expression on skin endothelia in atopic dermatitis:: Effects of TNF-α and IL-4
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DOI：
10.1016/s0091-6749(98)70136-8
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发表时间：
1998-09-01
影响因子：
14.2
通讯作者：
Bruijnzeel-Koomen, CAFM
中科院分区：
文献类型：
--
作者：
de Vries, IJM;Langeveld-Wildschut, EG;Bruijnzeel-Koomen, CAFM
背景资料：特应性皮炎（AD）是一种以白细胞（如淋巴细胞和嗜酸性粒细胞）浸润为特征的皮肤炎性疾病。目的：研究AD患者皮肤内皮细胞（ECs）粘附分子的表达及其调控，探讨AD的发病机制。方法：以荆豆凝集素1（Ulex europaeus agglutin 1）为泛内皮标志物，采用免疫组化方法检测ECs粘附分子的表达。结果：AD患者皮肤内皮细胞粘附分子表达水平明显高于正常对照组（P < 0. 05），而正常对照组（P < 0. 05）。结论：AD患者皮肤内皮细胞粘附分子表达水平明显高于正常对照组（P < 0. 05）。血管细胞粘附分子-1（VCAM-1）、E-选择素和P-选择素在非特应性个体的皮肤中未发现，而这些表面分子的表达在AD患者的非病变皮肤中观察到，并且在病变皮肤中或在表皮应用空气变应原后甚至更明显，在来自人脐带静脉的大血管EC（HUVEC）和来自皮肤的人微血管EC（HMEC-1）上检测粘附分子表达的诱导，TNF-α非常有效地上调粘附分子的表达在体外EC细胞类型。为了验证TNF-α的体内相关性，我们在皮肤中进行了TNF-α染色。在非特应性皮肤的真皮中观察到TNF-α，包括含糜酶的肥大细胞和CD 68+巨噬细胞。AD患者皮肤中含TNF α细胞数量的增加伴随着粘附分子表达的增加。IL-4由于其IgE和VCAM-1诱导特性而被认为在特应性疾病中是重要的。然而，IL-4的加入未能诱导HMEC-1上VCAM-1的表达，尽管在同一组实验中，证实了IL-4对HUVEC上VCAM-1表达的明显诱导，流式细胞术揭示了HMEC-1上不存在IL-4受体α链，而它们在HUVEC上存在，皮肤切片的免疫组织化学检查显示IL-4 R α链抗体不与EC结合。我们的结论是，粘附分子的表达增加，在皮肤的AD患者。最有可能的是，这种增加的表达不是IL-4对皮肤内皮的（直接）作用，而是其他细胞因子，如TNF-α，可能是这种增加的粘附分子表达的原因。持续的粘附分子表达可能以非抗原特异性的方式促进T细胞外渗，从而解释了AD患者非病变皮肤中T细胞数量增加的原因。
Background: Atopic dermatitis (AD) is characterized by skin infiltrates of leukocytes, such as lymphocytes and eosinophils.Objective: To describe the mechanisms determining this inflammatory process, we have analyzed expression of adhesion molecules and their regulation on skin endothelial cells (ECs).Methods: Expression of adhesion molecules on ECs was analyzed by immunohistochemistry by using Ulex europaeus agglutin 1 as a pan-endothelial marker.Results: Vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin were not found in skin of nonatopic individuals, whereas expression of these sur face molecules was observed in nonlesional skin of patients with AD and was even more pronounced in lesional skin or after epicutaneous application of aeroallergen, Induction of adhesion molecule expression was examined on both macrovascular ECs from human umbilical cord vein (HUVECs) and human microvascular ECs (HMEC-1) from skin, TNF-alpha very potently upregulated adhesion molecule expression in vitro on both EC cell types. To verify the in vivo relevance of TNF-alpha, we performed TNF-alpha staining in the skin. TNF-alpha was observed in the dermis of nonatopic skin, both in chymase-containing mast cells and CD68+ macrophages. The increase in the number of TNF alpha-containing cells was concomitant with the increase in adhesion molecule expression in the skin of patients with AD. IL-4 is supposed to be important in atopic diseases because of its IgE- and VCAM-1-inducing properties. However, IL-4 addition failed to induce VCAM-1 expression on HMEC-1, although in the same set of experiments, a clear induction of VCAM-1 expression by IL-4 on HUVECs was demonstrated, Flow cytometry revealed the absence of IL-4 receptor alpha-chains on HMEC-1 and their presence on HUVECs, Immunohistochemistry examination on skin sections showed no binding of the IL-4R alpha-chain antibodies to ECs.Conclusion: We conclude that adhesion molecule expression is increased in the skin of patients with AD. Most probably, this increased expression is not a (direct) effect of IL-4 on skin endothelium, but other cytokines, such as TNF-alpha, might be responsible for this increased adhesion molecule expression. Continuous adhesion molecule expression may facilitate T-cell extravasation in a nonantigen-specific manner, thus explaining the presence of increased T-cell numbers in nonlesional skin of patients with AD.