Extracellular ATP acting at the P2X7 receptor inhibits secretion of soluble HLA-G from human monocytes.
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-P2X(7) mAb, thus pointing to a specific role of the P2X(7) 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.
Rizzo
Roberta
R
Department of Experimental and Diagnostic Medicine, Laboratory of Immunogenetics, Section of Medical Genetics, University of Ferrara, Via L. Borsari 46, Ferrara I-44100, Italy. rbr@unife.it
Ferrari
Davide
D
Melchiorri
Loredana
L
Stignani
Marina
M
Gulinelli
Sara
S
Baricordi
Olavio R
OR
Di Virgilio
Francesco
F
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology* / Q000378:metabolism; D006680:HLA Antigens / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism* / Q000502:physiology; D058486:Receptors, Purinergic P2X7
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C508609:IL10 protein, human; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D016753:Interleukin-10