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The A_2B Adenosine Receptor Impairs the Maturation and Immunogenicity of Dendritic Cells ¹

Jeffrey M. Wilson^*, William G. Ross^*, Oma N. Agbai^*, Renea Frazier, Robert A. Figler, Jayson Rieger, Joel Linden^* and Peter B. Ernst^2,*

^* Department of Medicine, University of Virginia, Charlottesville, VA 22908; and Adenosine Therapeutics Group, PGxHealth, a Division of Clinical Data, Charlottesville, VA 22908

The endogenous purine nucleoside adenosine is an important antiinflammatory mediator that contributes to the control of CD4⁺ T cell responses. While adenosine clearly has direct effects on CD4⁺ T cells, it remains to be determined whether actions on APC such as dendritic cells (DC) are also important. In this report we characterize DC maturation and function in BMDC stimulated with LPS in the presence or absence of the nonselective adenosine receptor agonist NECA (5'-N-ethylcarboxamidoadenosine). We found that NECA inhibited TNF- and IL-12 in a concentration-dependent manner, whereas IL-10 production was increased. NECA-treated BMDC also expressed reduced levels of MHC class II and CD86 and were less effective at stimulating CD4⁺ T cell proliferation and IL-2 production compared with BMDC exposed to vehicle control. Based on real-time RT-PCR, the A_2A adenosine receptor (A_2AAR) and A_2BAR were the predominant adenosine receptors expressed in BMDC. Using adenosine receptor subtype selective antagonists and BMDC derived from A_2AAR^–/– and A_2BAR^–/–mice, it was shown that NECA modulates TNF-, IL-12, IL-10, and CD86 responses predominantly via A_2BAR. These data indicate that engagement of A_2BAR modifies murine BMDC maturation and suggest that adenosine regulates CD4⁺ T cell responses by selecting for DC with impaired immunogencity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Crohn’s and Colitis Foundation of America (CCFA); by National Institutes of Health Grants DK50980, AI069880, AI070491 (to P.B.E.), and AI075526 (to Richard Guerrant for ATL compound development); and by the Immunology and Cell Isolation Core as well as the Molecular Biology Core of the University of Virginia Digestive Health Research Center (DK67629).

² Address correspondence and reprint requests to Dr. Peter B. Ernst, University of Virginia, Department of Medicine, P.O. Box 100708, Charlottesville, VA 22908. E-mail address: pernst{at}virginia.edu

³ Abbreviations used in this paper: AR, adenosine receptor; ATL692, 1,3-dialkyl-8-hetero substituted xanthine; DC, dendritic cell; NECA, 5'-N-ethylcarboxamidoadenosine; SCH58261, 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine; ZM241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-][1,3,5] triazin-5-ylamino]ethyl)phenol.

⁴ The online version of this article contains supplemental material.