Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression.
Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3beta (MIP-3beta) and induces them to retain responsiveness to MIP-1alpha after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D016572:Cyclosporine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases