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production via adenosine A2a receptor-dependent and independent mechanisms
1
* Inotek Corp., Beverly, Massachusetts 01915, USA;
Department of Surgery, UMD-New Jersey Medical School, Newark, New Jersey 07103, USA; and
Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA
1Correspondence: Department of Surgery, UMD-New Jersey Medical School, 185 South Orange Ave., University Heights, Newark, NJ 07103, USA. E-mail: haskoge{at}umdnj.edu
Interleukin 12 (IL-12) is a crucial cytokine in the regulation of T
helper 1 vs. T helper 2 immune responses. In the present study, we
investigated the effect of the endogenous purine nucleoside adenosine
on the production of IL-12. In mouse macrophages, adenosine suppressed
IL-12 production. Although the order of potency of adenosine receptor
agonists suggested the involvement of A2a receptors, data
obtained with A2a receptor-deficient mice showed that the
adenosine suppression of IL-12 and even TNF-
production is only
partly mediated by A2a receptor ligation. Studies with
adenosine receptor antagonists or the adenosine uptake blocker
dipyridamole showed that adenosine released endogenously also decreases
IL-12. Although adenosine increases IL-10 production, the inhibition of
IL-12 production is independent of the increased IL-10. The mechanism
of action of adenosine was not associated with alterations of the
activation of the p38 and p42/p44 mitogen-activated protein kinases or
the phosphorylation of the c-Jun terminal kinase. Adenosine failed to
affect steady-state levels of either IL-12 p35 or p40 mRNA, but
augmented IL-10 mRNA levels. In summary, adenosine inhibits IL-12
production via various adenosine receptors. These results support the
notion that adenosine-based therapies might be useful in certain
autoimmune and/or inflammatory diseases.—Haskó, G., Kuhel,
D. G., Chen, J.-F., Schwarzschild, M. A., Deitch, E. A.,
Mabley, J. G., Marton, A., Szabó, C. Adenosine inhibits
IL-12 and TNF- production via adenosine A2a
receptor-dependent and independent mechanisms.
Key Words: inflammatory mediators • cytokines • T lymphocytes • inflammation
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