Extracellular ATP Acting at the P2X7 Receptor Inhibits Secretion of Soluble HLA-G from Human Monocytes

Abstract

Bacterial LPS induces the release of ATP from immune cells. Accruing evidence suggests that extracellular ATP participates in the inflammatory response as a proinflammatory mediator by activating the inflammasome complex, inducing secretion of cytokines (IL-1, IL-18) and cell damaging agents such as oxygen radicals, cationic proteins, and metalloproteases. It is not known whether ATP can also act as a proinflammatory mediator by inhibiting production of molecules down-modulating the immune response. Here, we show that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes. The effect of ATP was mimicked by BzATP (3′-O-(4-benzoyl)benzoyl-ATP) and greatly reduced by pretreatment with oATP (periodate-oxidized ATP), KN-62 (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine), and an anti-P2X7 mAb, thus pointing to a specific role of the P2X7 receptor. The effect of ATP was time- and dose-dependent and was not due to a decrease in expression of IL-10 receptor. Inhibition by ATP was reverted by supplementation of culture medium with exogenous IL-10. Due to the well-known immunosuppressive activity of IL-10 and soluble HLA-G, this novel effect of ATP might be relevant for the pathophysiology and therapy of inflammatory disorders.

P2X ion channel receptors and inflammation

“…P2X7 receptors mediate transforming growth factor β secretion. P2X7 receptor activation also releases a potent immunosuppressive agent, HLA-G [66,67] and vascular endothelial growth factor, another major player in inflammation [68]. Another function of P2X7 receptors in inflammation is the activation of transcription factors such as NFkB and NFAT [69,70].…”

A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system

“…Non-apoptotic cell death (which may restrict trophoblast invasion in the presymptomatic stage of preeclampsia) results in higher levels of ATP in the extracellular milieu. Extracellular ATP inhibits LPSstimulated production of the immunosuppressive sHLA-G, via the P2X receptor (Rizzo et al 2009). The P2X7 receptor has been implicated in the production of tissue factor-expressing microparticles (Baroni et al 2007), and MHC Class II-expressing exosomes (Qu et al 2009).…”

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

“…Consistent with this, P2X7 activation induced the release of MHC class II molecule-containing microvesicles and exosomes from murine macrophages and dendritic cells [91,92], but did not induce a loss of MHC class II molecules from the surface of CLL cells [34]. Finally, P2X7 activation inhibited the release of the non-classical MHC molecule, soluble human leukocyte antigen-G, from LPS-activated peripheral blood mononuclear cells [93]. Collectively, these studies demonstrate a complex role for P2X7 activation in the loss of MHC molecules from cells, and it remains to be determined if P2 receptor activation induces ectodomain shedding of MHC molecules.…”