53: Inhibition of interleukin-15 dependent cytotoxic T-cell proliferation by the action of adenosine on dendritic cells Conference Paper uri icon

abstract

  • Dendritic cells (DCs) regulate the immune response through production of various cytokines and signaling molecules, among which is IL-15, an important NK and cytotoxic T-cell (CTL) activator and survival factor. At the site of immune reaction, adenosine is produced from ATP by CD39 and CD73, ecto-enzymes expressed on regulatory T-cells (Treg). The aim of this present study was to examine the effect of adenosine on IL-15 production by DCs and the implication of this effect on CTL proliferation. Bone marrow derived DCs (BMDCs) were isolated from ICR mice. BMDCs were exposed to various adenosine receptor agonists/antagonist prior to stimulation with LPS and interferon- γ (IFN- γ ). Levels of cAMP, IL-15 and IL-15 receptor α chain (IL-15R α ) were measured using QPCR and/or ELISA. To assess the effect on CTL proliferation BMDCs were gamma-radiated and co-cultured with CTLL-2, a cytotoxic T-cell line, in the presence or absence of adenosine. Stimulation of BMDCs with LPS and IFN- γ increased IL-15 and IL-15R α levels. Treatment of stimulated BMDCs with adenosine significantly reduced IL-15/IL-15R α mRNA and protein levels. This down-regulatory effect was blocked by the combination of ZM 241385, an A 2 A R antagonist, and MRS1754, an A 2 B R antagonist, while addition of only one of them separately yielded a partial inhibitory effect. Treatment of BMDCs with adenosine receptor agonists increased cAMP levels, and di-butirilic-cAMP, a stable cAMP analog, effectively reduced IL-15R α levels. Finally, treatment of BMDCs with adenosine, before stimulation and co-culture, significantly reduced PBMC-dependent CTLL-2 proliferation. Our data indicate that adenosine acting through A 2 A R and A 2 B R by elevation of cAMP suppresses IL-15 and IL-15R α levels in activated DCs and restrains CTL proliferation. These finding can set a pharmacological base for CTL dependent pathologies such as graft rejection treatment.

publication date

  • January 1, 2013

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