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* New England Inflammation and Tissue Protection Institute at Northeastern University, Boston, MA 02115;
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Center for Clinical Pharmacology, Department of Pharmacology and Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
The genetic elimination of A2A adenosine receptors (A2AR) was shown to disengage the critical immunosuppressive mechanism and cause the dramatic exacerbation of acute inflammatory tissue damage by T cells and myeloid cells. This prompted the evaluation of the proinflammatory vs the anti-inflammatory effects of the widely consumed behavioral drug caffeine, as the psychoactive effects of caffeine are mediated largely by its antagonistic action on A2AR in the brain. Because caffeine has other biochemical targets besides A2AR, it was important to test whether the consumption of caffeine during an acute inflammation episode would lead to the exacerbation of immune-mediated tissue damage. We examined acute and chronic treatment with caffeine for its effects on acute liver inflammation. It is shown that caffeine at lower doses (10 and 20 mg/kg) strongly exacerbated acute liver damage and increased levels of proinflammatory cytokines. Because caffeine did not enhance liver damage in A2AR-deficient mice, we suggest that the potentiation of liver inflammation was mediated by interference with the A2AR-mediated tissue-protecting mechanism. In contrast, a high dose of caffeine (100 mg/kg) completely blocked both liver damage and proinflammatory cytokine responses through an A2AR-independent mechanism. Furthermore, caffeine administration exacerbated liver damage even when mice consumed caffeine chronically, although the extent of exacerbation was less than in "naive" mice that did not consume caffeine before. This study suggests an unappreciated "man-made" immunological pathogenesis whereby consumption of the food-, beverage-, and medication-derived adenosine receptor antagonists may modify an individual’s inflammatory status and lead to excessive organ damage during acute inflammation.
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 Grants CA112561, CA111985, and AT002788 from the National Institutes of Health (to M.S.).
2 Address correspondence and reprint requests to Dr. Akio Ohta, New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113 Mugar Health Sciences Building, Boston, MA 02115. E-mail address: a.ohta{at}neu.edu
3 Abbreviations used in this paper: A2AR, A2A adenosine receptor; ALT, alanine aminotransferase; A1R, A1 adenosine receptor; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine.
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