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

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 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.

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A2B receptor

“…This action is mediated by a rise in cAMP and involves the P2Y 11 receptor [9,10,12,14]. However, no functional P2Y 11 gene has been found in the murine genome.…”

“…In addition, adenine nucleotides affect the production of chemokines (CCL22, CCL5), chemokine receptors (CCR7, CCR5) and the migration of DC [12,13]. Pharmacological data suggest that ATP exerts its actions through the cyclic adenosine 3 0 ,5 0 -monophosphate (cAMP) signalling pathway by activating the P2Y 11 receptor [9,[12][13][14].…”

“…Nucleotides and nucleosides released in the extracellular space by necrotic cells or activated immune cells at the site of inflammation are thought to control the immune response [4,5]. Adenosine exerts its actions by activating P1 (A 1 , A 2A , A 2B and A 3 ) receptors while nucleotides bind to P2Y (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y [11][12][13][14] or P2X (P2X 1-7 ) receptors (for review see [6]). We and others have shown that adenosine triphosphate (ATP) promotes a semi-maturation state of human monocyte-derived DC that could take part in tolerance.…”

P2 receptor-mediated signaling in mast cell biology

“…Moreover, ATP-induced degranulation of MC/9 cells was not mediated by PKC [70]. P2Y 11 receptor seems the only P2Y receptor that is linked to adenylate cyclase/cAMP signaling in the human system [73]. The impact of P2Y 11 receptor activation on cytokine release will be discussed below.…”

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

“…Adenosine receptor ligation on monocyte/macrophages and DCs inhibits the production of IL-12, which leads to impairment of T cell priming and suppression of antitumor immune response [88]. IL-12 is considered as an important antitumor cytokine, which has potent antitumor effects in mouse models of melanoma, sarcoma, kidney cancer, lung cancer, colon cancer, and ovarian cancer [89][90][91][92][93][94].…”