Abstract
IntroductionIFNA1 (interferon alpha) is a key cytokine regulating the activity of numerous immune cells. Plasmacytoid dendritic cells (pDCs) as natural interferon-producing cells play critical roles as sensors of pathogens and link innate to adaptive immunity. CpG motifs within DNA sequences activating toll-like receptor 9 (TLR9) are the main stimuli eliciting IFNA1 secretion from pDCs. Adrenergic substances are capable of differentially modulating the response from various immune cells. Hence, the aim of this study was to examine how adrenoceptor stimulation influences TLR9-induced IFNA1 secretion from human pDCs.MethodsPBMCs generated from human whole blood and pDCs enriched from buffy coats were stimulated with LPS and CpG-ODN 2336 in the presence or absence of epinephrine and different adrenoceptor antagonists. Secretion of TNF and IFNA1 was measured by ELISA. Flow cytometry was used to determine efficacy of pDC enrichment and adrenoceptor expression of PBMC subsets. The influence of modified IFNA1 secretion on NK cell activity was evaluated using a colorimetric tumor cell lysis assay.ResultsTLR9-induced IFNA1 secretion as well as TLR4-induced TNF secretion from PBMCs was dose-dependently attenuated by coincubation with epinephrine. Combination with different specific adrenoceptor antagonists revealed that this effect was mediated by the adrenoceptor β2 (ADRB2). Since flow cytometric analysis could exclude the presence of ADRB2 on pDCs, highly enriched pDCs lacked any visible impact of adrenoceptor stimulation on TLR9-induced IFNA1 release. Combination of pDCs with PBMCs restored the effect, even when they were separated by a permeable membrane. Suppression of TLR9-mediated IFNA1 secretion from PBMCs by adrenoceptor stimulation reduced the lytic activity of NK cells on K562 tumor cells.ConclusionWe provide insights into the underlying mechanisms of the interrelation between immune responses and pharmacological agents widely used in clinical practice. Our results have implications for the future treatment of human patients, in which the endogenous immune response plays a pivotal role, such as during viral infections, inflammatory diseases and cancers.
Highlights
IFNA1 is a key cytokine regulating the activity of numerous immune cells
toll-like receptor 9 (TLR9)-induced IFNA1 secretion as well as TLR4-induced TNF secretion from peripheral blood mononuclear cells (PBMCs) was dose-dependently attenuated by coincubation with epinephrine
Since flow cytometric analysis could exclude the presence of adrenoceptor b2 (ADRB2) on Plasmacytoid dendritic cells (pDCs), highly enriched pDCs lacked any visible impact of adrenoceptor stimulation on TLR9-induced IFNA1 release
Summary
IFNA1 (interferon alpha) is a key cytokine regulating the activity of numerous immune cells. Plasmacytoid dendritic cells (pDCs) as natural interferon-producing cells play critical roles as sensors of pathogens and link innate to adaptive immunity. The aim of this study was to examine how adrenoceptor stimulation influences TLR9-induced IFNA1 secretion from human pDCs. Dendritic cells (DCs) play a critical role as sensors of pathogens and tissue injury. Dendritic cells (DCs) play a critical role as sensors of pathogens and tissue injury Besides classical DCs (cDCs), a second set of DCs has been characterized in recent years [1] These plasmacytoid DCs (pDCs) were shown to be the natural interferon-producing cells (IPCs), which generate the majority of circulating type I interferons (type I IFNs) upon viral infections, about 200–1000 fold more than any other blood cell [1,2]. PDCs enter the lymph nodes to exert their functions [1,4]
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