the cyclophilin-binding agent sanglifehrin a is a dendritic cell chemokine and migration inhibitorcyclophilin-binding代理sanglifehrin树突细胞趋化因子和迁移抑制剂.pdfVIP

The Cyclophilin-Binding Agent Sanglifehrin A Is a Dendritic Cell Chemokine and Migration Inhibitor 1 1 2 1 1 1 Sabrina N. Immecke , Nelli Baal , Jochen Wilhelm , Juliane Bechtel , Angela Knoche , Gregor Bein , Holger Hackstein1* 1 Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Giessen, Germany, 2 Department of Pathology, Justus-Liebig-University Giessen, Giessen, Germany Abstract 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 CCL1