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.
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 E(2) by cyclic adenosine monophosphate (cAMP)-elevating EP2/EP4 receptors. As a consequence, DCs were selectively impaired in their ability to induce interferon-gamma (IFN-gamma) in naive T cells but continued to promote IFN-gamma 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.
Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria 3084, Australia.
Max
M
Schnurr
Tracey
T
Toy
Amanda
A
Shin
Moritz
M
Wagner
Jonathan
J
Cebon
Eugene
E
Maraskovsky
D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D005110:Extracellular Space / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009975:Orthomyxoviridae / Q000276:immunology; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
C508840:IL23A protein, human; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; C464565:MYDGF protein, human; D018048:Receptors, Purinergic P2; D018664:Interleukin-12; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D000242:Cyclic AMP