Topographical and biological evidence revealed FTY720-mediated anergy-polarization of mouse bone marrow-derived dendritic cells in vitro

PLoS One. 2012;7(5):e34830. doi: 10.1371/journal.pone.0034830. Epub 2012 May 31.

Abstract

Abnormal inflammations are central therapeutic targets in numerous infectious and autoimmune diseases. Dendritic cells (DCs) are involved in these inflammations, serving as both antigen presenters and proinflammatory cytokine providers. As an immuno-suppressor applied to the therapies of multiple sclerosis and allograft transplantation, fingolimod (FTY720) was shown to affect DC migration and its crosstalk with T cells. We posit FTY720 can induce an anergy-polarized phenotype switch on DCs in vitro, especially upon endotoxic activation. A lipopolysaccharide (LPS)-induced mouse bone marrow-derived dendritic cell (BMDC) activation model was employed to test FTY720-induced phenotypic changes on immature and mature DCs. Specifically, methods for morphology, nanostructure, cytokine production, phagocytosis, endocytosis and specific antigen presentation studies were used. FTY720 induced significant alterations of surface markers, as well as decline of shape indices, cell volume, surface roughness in LPS-activated mature BMDCs. These phenotypic, morphological and topographical changes were accompanied by FTY720-mediated down-regulation of proinflammatory cytokines, including IL-6, TNF-α, IL-12 and MCP-1. Together with suppressed nitric oxide (NO) production and CCR7 transcription in FTY720-treated BMDCs with or without LPS activation, an inhibitory mechanism of NO and cytokine reciprocal activation was suggested. This implication was supported by the impaired phagocytotic, endocytotic and specific antigen presentation abilities observed in the FTY720-treated BMDCs. In conclusion, we demonstrated FTY720 can induce anergy-polarization in both immature and LPS-activated mature BMDCs. A possible mechanism is FTY720-mediated reciprocal suppression on the intrinsic activation pathway and cytokine production with endpoint exhibitions on phagocytosis, endocytosis, antigen presentation as well as cellular morphology and topography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / drug effects
  • Bone Marrow Cells / cytology*
  • Cell Survival / drug effects
  • Cytokines / biosynthesis
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Fingolimod Hydrochloride
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Nitric Oxide / biosynthesis
  • Phagocytosis / drug effects
  • Phenotype
  • Propylene Glycols / pharmacology*
  • Receptors, CCR7 / biosynthesis
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology

Substances

  • Ccr7 protein, mouse
  • Cytokines
  • Lipopolysaccharides
  • Propylene Glycols
  • Receptors, CCR7
  • Nitric Oxide
  • Fingolimod Hydrochloride
  • Sphingosine