The cyclophilin-binding agent Sanglifehrin A is a dendritic cell chemokine and migration inhibitor

PLoS One. 2011 Mar 31;6(3):e18406. doi: 10.1371/journal.pone.0018406.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism
  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Movement / drug effects*
  • Cells, Cultured
  • Chemokines / metabolism*
  • Cyclophilins / metabolism*
  • Cytokines / metabolism
  • Dendritic Cells / cytology*
  • Dendritic Cells / drug effects*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Lactones / metabolism
  • Lactones / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding
  • Receptors, CCR7 / metabolism
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacology

Substances

  • CCR7 protein, human
  • Chemokines
  • Cytokines
  • Lactones
  • Receptors, CCR7
  • Spiro Compounds
  • sanglifehrin A
  • ADP-ribosyl Cyclase 1
  • Cyclophilins