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

• DOI: 10.1182/blood-2004-05-1718
• Publication Date: 2004-10-15T00:26:05Z
• Authors: Max Schnurr; Tracey Toy; Amanda Shin; Moritz Wagner; Jonathan Cebon; Eugene Maraskovsky
• Keywords: 0301 basic medicine; Receptors, Purinergic P2; Interleukins; Down-Regulation; Dendritic Cells; Orthomyxoviridae; Interleukin-12; Interleukin-23; Resting Phase, Cell Cycle; Monocytes; 3. Good health; Interferon-gamma; Mice; 03 medical and health sciences; Adenosine Triphosphate; Cyclic AMP; Escherichia coli; Interleukin-23 Subunit p19; Animals; Humans; Extracellular Space; Immunologic Memory; Cells, Cultured

AbstractThe 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-γ (IFN-γ) in naive T cells but continued to promote IFN-γ 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.