Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms

FASEB J. 2000 Oct;14(13):2065-74. doi: 10.1096/fj.99-0508com.

Abstract

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-alpha 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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / pharmacology*
  • Animals
  • Interleukin-10 / biosynthesis
  • Interleukin-12 / biosynthesis*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects*
  • Macrophages, Peritoneal / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinases / metabolism
  • Purinergic P1 Receptor Agonists
  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1 / deficiency
  • Receptors, Purinergic P1 / genetics
  • Receptors, Purinergic P1 / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis*

Substances

  • Lipopolysaccharides
  • Purinergic P1 Receptor Agonists
  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-12
  • Mitogen-Activated Protein Kinases
  • Adenosine