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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1582-1589.
Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-05-1718.
 Previous Article | Table of Contents | Next Article 
IMMUNOBIOLOGY
Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway
Max Schnurr,
Tracey Toy,
Amanda Shin,
Moritz Wagner,
Jonathan Cebon, and
Eugene Maraskovsky
From the Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria; and CSL Limited, Parkville, Victoria, Australia.
The interleukin-12 (IL-12) cytokine family plays important roles in the orchestration of innate and adaptive immunity by dendritic cells (DCs). The regulation of IL-12 expression has been thoroughly studied, but little is known about factors governing the expression of IL-23 and IL-27, 2 novel IL-12 family members acting on memory and naive T cells, respectively. We report that the expression of these cytokines by DCs was critically dependent on the mode of activation. DC activation by CD40L predominantly induced IL-12. Ligands of the Toll-like receptor (TLR) 3 and TLR4 induced IL-12 and IL-27, whereas exposure to intact Escherichia coli resulted in high expression of IL-12, IL-27, and IL-23. The nucleotide adenosine triphosphate (ATP) has been shown to inhibit IL-12 production by P2 receptors. We found that ATP also inhibited IL-27 expression but enhanced IL-23 expression. Interestingly, the reciprocal regulation of IL-12/IL-27 and IL-23 by ATP was mediated by 2 distinct P2 receptors and was also induced by prostaglandin E2 by cyclic adenosine monophosphate (cAMP)–elevating EP2/EP4 receptors. As a consequence, DCs were selectively impaired in their ability to induce interferon- (IFN-) in naive T cells but continued to promote IFN- and IL-17 production in memory T cells. These studies identify P2 receptors as promising targets for the design of novel strategies to manipulate specific stages of T-cell responses and to treat IL-12– and IL-23–mediated disorders.
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