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Title: 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.
Austin Authors: Schnurr, Max;Toy, Tracey;Shin, Amanda;Wagner, Moritz;Cebon, Jonathan S ;Maraskovsky, Eugene
Affiliation: Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria 3084, Australia
Issue Date: 14-Oct-2004
Publication information: Blood 2004; 105(4): 1582-9
Abstract: 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.
Gov't Doc #: 15486065
DOI: 10.1182/blood-2004-05-1718
Journal: Blood
Type: Journal Article
Subjects: Adenosine Triphosphate.pharmacology.physiology
Cells, Cultured
Cyclic AMP.physiology
Dendritic Cells.immunology.metabolism.secretion
Escherichia coli.immunology
Extracellular Space.metabolism.physiology
G0 Phase.immunology
Immunologic Memory
Interferon-gamma.antagonists & inhibitors.biosynthesis
Interleukin-12.antagonists & inhibitors.biosynthesis
Interleukin-23 Subunit p19
Receptors, Purinergic P2.physiology
Signal Transduction.immunology
T-Lymphocyte Subsets.cytology.immunology.metabolism
Appears in Collections:Journal articles

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