Institute for Clinical Immunology and Transfusion Medicine, Department of Pathology, Justus-Liebig-University Giessen, Giessen, Germany.
PLoS One. 2011 Mar 31;6(3):e18406. doi: 10.1371/journal.pone.0018406.
Sanglifehrin A (SFA) is a cyclophilin-binding immunosuppressant but the immunobiology of action is poorly understood. We and others have reported that SFA inhibits IL-12 production and antigen uptake in dendritic cells (DC) and exhibits lower activity against lymphocytes. Here we show that SFA suppresses DC chemokine production and migration. Gene expression analysis and subsequent protein level confirmation revealed that SFA suppressed CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DC (moDC). A systems biology analysis, Onto Express, confirmed that SFA interferes with chemokine-chemokine receptor gene expression with the highest impact. Direct comparison with the related agent cyclosporine A (CsA) and dexamethasone indicated that SFA uniquely suppresses moDC chemokine expression. Competitive experiments with a 100-fold molar excess of CsA and with N-Methyl-Val-4-cyclosporin, representing a nonimmunosuppressive derivative of CsA indicated chemokine suppression through a cyclophilin-A independent pathway. Functional assays confirmed reduced migration of CD4+ Tcells and moDCs to supernatant of SFA-exposed moDCs. Vice versa, SFA-exposed moDC exhibited reduced migration against CCL19. Moreover, SFA suppressed expression of the ectoenzyme CD38 that was reported to regulate DC migration and cytokine production. These results identify SFA as a DC chemokine and migration inhibitor and provide novel insight into the immunobiology of SFA.
桑福拉嗪 A（SFA）是一种亲环素结合型免疫抑制剂，但作用的免疫生物学机制尚不清楚。我们和其他人已经报道，SFA 抑制树突状细胞（DC）中 IL-12 的产生和抗原摄取，并对淋巴细胞的活性较低。在这里，我们表明 SFA 抑制 DC 趋化因子的产生和迁移。基因表达分析和随后的蛋白水平确认表明，SFA 抑制人单核细胞衍生的 DC（moDC）中 CCL5、CCL17、CCL19、CXCL9 和 CXCL10 的表达。系统生物学分析 Onto Express 证实，SFA 干扰趋化因子-趋化因子受体基因表达的影响最大。与相关药物环孢素 A（CsA）和地塞米松的直接比较表明，SFA 独特地抑制 moDC 趋化因子的表达。用 CsA 和 N-甲基-Val-4-环孢素（代表 CsA 的非免疫抑制衍生物）进行 100 倍摩尔过量的竞争性实验表明，趋化因子抑制是通过亲环素 A 独立途径发生的。功能测定证实，SFA 暴露的 moDC 上清液中 CD4+T 细胞和 moDC 的迁移减少。相反，SFA 暴露的 moDC 对 CCL19 的迁移减少。此外，SFA 抑制了据报道调节 DC 迁移和细胞因子产生的外切酶 CD38 的表达。这些结果表明 SFA 是一种 DC 趋化因子和迁移抑制剂，并为 SFA 的免疫生物学提供了新的见解。
