Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

• Published in: The Journal of immunology (1950) Vol. 195; no. 2; pp. 651 - 660
• Main Authors: Chadet, Stéphanie, Ivanes, Fabrice, Benoist, Lauriane, Salmon-Gandonnière, Charlotte, Guibon, Roseline, Velge-Roussel, Florence, Babuty, Dominique, Baron, Christophe, Roger, Sébastien, Angoulvant, Denis
• Format: Journal Article
• Language: English
• Published: United States Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists 15.07.2015
• Subjects: Adenosine Triphosphate - pharmacology; Cell Hypoxia; Cellular Biology; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - immunology; Immunology; Immunosuppression; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Life Sciences; Oxygen - pharmacology; Primary Cell Culture; Purinergic Antagonists - pharmacology; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - immunology; RNA, Small Interfering - genetics; RNA, Small Interfering - immunology; Signal Transduction; Time Factors; Transcription, Genetic
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500197

High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.