Stimulation of purinergic receptors modulates chemokine expression in human keratinocytes

Saveria Pastore, Francesca Mascia, Sara Gulinelli, Sylvia Forchap, Cristina Dattilo, Elena Adinolfi, Giampiero Girolomoni, Francesco Di Virgilio, Davide Ferrari

Research output: Contribution to journalArticlepeer-review

Abstract

ATP is abundantly released from stressed or damaged cells in response to mechanical stimulation, bacteria, or noxious agents. In this study, we have investigated the possible involvement of P2 receptors (receptor for extracellular nucleotides) in the expression and release of inflammatory mediators by human keratinocytes. Notably, extracellular ATP displayed a complex regulation of IFN-γ-stimulated chemokine expression, with upregulation of CC chemokine ligand 2 (CCL2), CCL5 and CXC chemokine ligand 8 (CXCL8), and suppression of the receptor CXC chemokine receptor 3 (CXCR3), CXCL9, CXCL10, and CXCL11. The effect of ATP was mimicked by ADP and adenosine-5′-O-3- thiotriphosphate, whereas 2′,3′-O-(4-benzoylbenzoyl) ATP (BzATP) downmodulated all chemokines investigated. UTP had no effect on IFN-γ-stimulated chemokine secretion. The broad-spectrum P2 receptor antagonist suramin and the selective P2Y1 inhibitor adenosine 3′-phosphate 5′-phosphosulfate counteracted the effect of ATP on secretion of all the chemokines examined, whereas pyridoxal phosphate 6-azophenyl 2′,4′-disulfonic acid and KN62 (1-[N,O-bis(5- isoquinoline sulfonyl)-N-methyl-L-tyrosyl] 4 phenylpiperazine) partially prevented the inhibitory effect of ATP on CXCL10 secretion, but on the other hand potentiated the ATP-stimulatory effect on CCL5, CCL2, and CXCL8 release. In lesional skin of psoriasis and atopic dermatitis patients, intense P2X 7 reactivity was confined to the cell membrane of the basal layer, whereas diffuse P2Y1 immunostaining was found throughout the epidermis. Collectively, our data suggest that the orchestrated activation of distinct P2Y and P2X receptors modulates skin inflammation.

Original languageEnglish
Pages (from-to)660-667
Number of pages8
JournalJournal of Investigative Dermatology
Volume127
Issue number3
DOIs
Publication statusPublished - Mar 2007

ASJC Scopus subject areas

  • Dermatology

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