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* Department of Microbiology and Infectious Diseases, Immunology Research Group and Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada;
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and
Department of Internal Medicine, Yale University, New Haven, CT 06520
Adenosine is a suppressive agent that protects the host from excessive tissue injury associated with strong inflammation. In tissue stress, higher levels of adenosine signal through adenosine receptors to exert strong anti-inflammatory effects, and thus protect host cells. Existing evidence also suggests that elevated adenosine potently down-regulates the activation of lymphocytes during inflammation. This notion, however, is in contrast with another basic observation that the immune system is highly activated precisely under the same circumstances against pathogens. In this study, we show that inflammatory responses of dendritic cells (DCs) are highly sensitive to adenosine suppression. However, they intrinsically carry high adenosine deaminase activity, which in turn degrades and removes adenosine from the surroundings, cutting off DCs from the suppression. This regulatory mechanism is important in DC responses to pathogen-associated molecular patterns and their activation of T cells. Our findings suggest a mechanism that DCs maintain their hyperreactive state in inflammation despite the general state of suppression, and reveal a regulatory role of adenosine deaminase in DC innate immune responses.
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 is supported by a grant from National Institutes of Health (to Y.S.) A.S. is supported by a Ph.D scholarship from Alberta Heritage Foundation for Medical Research.
2 Address correspondence and reprint requests to Dr. Yan Shi, B872 HSC, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. E-mail address: yshi{at}ucalgary.ca
3 Abbreviations used in this paper: P1R, P1 adenosine receptor; 8-PST, 8(p-sulfophenyl)theophylline; ADA, adenosine deaminase; BM, bone marrow; CPA, N6-cyclopentaladenosine; DC, dendritic cell; DCF, deoxycoformycin; EHNA, erythro-9-(2-hydroxy-3-nonyl) adenine; NBMPR, 6-((4-nitrobenzyl)thio)-9-
-D-ribofuranosylpurine; NECA, 5-(N-ethylcarboxamido) adenosine; PAMP, pathogen-associated molecular pattern.
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