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 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.
Highlights
The immunophilin-binding agents cyclosporine A (CsA), FK506 and rapamycin represent potent immunosuppressive agents that have revolutionized bone marrow and solid organ transplantation as well as treatment of autoimmune diseases
In this report we describe the results of the first systematic analysis of the immunobiological effects of the novel immunophilin-binding agent Sanglifehrin A (SFA) on human monocyte-derived dendritic cells (DC) using a combination of genome-wide expression profiling with subsequent confirmation on the protein level and functional in vitro and in vivo assays
CsA has been described to potently inhibit the binding of SFA to cyclophilin A [5] and we have found that CsA, in contrast to SFA, did not abrogate CCL5, CCL17 and CCL19 production in monocyte-derived DC (moDC). moDCs were preincubated for 1 hour with 10 mM CsA in order to saturate cylophilin binding sites
Summary
The immunophilin-binding agents cyclosporine A (CsA), FK506 and rapamycin represent potent immunosuppressive agents that have revolutionized bone marrow and solid organ transplantation as well as treatment of autoimmune diseases. Sanglifehrin A (SFA) is a novel immunophilin-binding immunosuppressive drug isolated from the actinomycetes strain Streptomyces A92-308110 exhibiting high affinity binding to Cyclophilin A, but unknown mechanism of action [1,2,3,4]. SFA does not affect the calcineurin phosphatase or the mammalian target of rapamycin and it does not inhibit purine or pyrimidine de novo synthesis [5]. In contrast to CsA, the immunobiology of SFA is not well understood. SFA is approximately 15–35-fold less potent than CsA at inhibiting T cell proliferation in mouse and human MLR cultures [5]. In contrast to CsA and FK506, SFA does not inhibit TCR-induced anergy [8]. SFA blocks IL-2 dependent proliferation in T cells [5]
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