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P2X7 receptor (P2X7R) stimulation by extracellular ATP is best known to active the NLRP3 inflammasome and release IL-1\u03b2, but stimulation also leads to release of other cytokines. As cytokine signaling by retinal pigmented epithelial (RPE) cells is implicated in retinal neurodegeneration, the role of P2X7R in release of cytokine IL-6 from RPE cells was investigated. P2X7R stimulation triggered IL-6 release from primary mouse RPE, human iPS-RPE and human ARPE-19 cells. IL-6 release was polarized, with predominant rise across apical membranes. IL-6 release was inhibited by P2X7R antagonists A438079, A839977, and AZ10606120, but not the NRTI lamivudine (3TC), P2X1R antagonist NF279, or P2Y1R antagonist MRS2179. P2X7R-mediated IL-6 release required extracellular Ca2+ and was blocked by Ca2+ chelator BAPTA. IL-6 release and Ca2+ elevation occurred rapidly, consistent with vesicular IL-6 staining in unstimulated cells. P2X7R stimulation did not trigger IL-1\u03b2 release in these unprimed cells. P2X7R-mediated IL-6 release was enhanced in RPE cells from the ABCA4\u2212\/\u2212 mouse model of retinal degeneration. In summary, P2X7R stimulation triggers rapid Ca2+-dependent IL-6 release across the apical membrane of RPE cells.<\/jats:p>","DOI":"10.3390\/cells9122537","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T20:50:22Z","timestamp":1606251022000},"page":"2537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Polarized Cytokine Release Triggered by P2X7 Receptor from Retinal Pigmented Epithelial Cells Dependent on Calcium Influx"],"prefix":"10.3390","volume":"9","author":[{"given":"Xiaolei","family":"Shao","sequence":"first","affiliation":[{"name":"Shenzhen Eye Hospital, School of Optometry, Shenzhen University, Shenzhen 518060, China"},{"name":"Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Guha","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wennan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith E.","family":"Campagno","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Beckel","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason A.","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Kirby Center for Molecular Ophthalmology and Center for Advanced Retinal and Ocular Therapeutics (CAROT), University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire H.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Peeters, P.M., Wouters, E.F., and Reynaert, N.L. 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