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Extracellular ATP Acting at the P2X₇ Receptor Inhibits Secretion of Soluble HLA-G from Human Monocytes¹

Roberta Rizzo^2,3,*, Davide Ferrari^2,,, Loredana Melchiorri^*, Marina Stignani^*, Sara Gulinelli^,, Olavio R. Baricordi^* and Francesco Di Virgilio^,

^* Department of Experimental and Diagnostic Medicine, Laboratory of Immunogenetics, Section of Medical Genetics, Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Italian Ministry of Education, University and Scientific Research, the Italian Association for Cancer Research, the Italian Space Agency, the Regione Emilia-Romagna ("Progetto Università-Regione" and "Moniter"), Telethon of Italy, and institutional funds from the University of Ferrara.

² R.R. and D.F. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Roberta Rizzo, Department of Experimental and Diagnostic Medicine, Laboratory of Immunogenetics, Section of Medical Genetics, University of Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy. E-mail address: rbr{at}unife.it

⁴ Abbreviations used in this paper: KN-62, 1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine; ADA, adenosine deaminase; BzATP, 3'-O-(4-benzoyl)benzoyl-ATP; oATP, periodate-oxidized ATP; PPADS, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid; LDH, lactate dehydrogenase.