{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:02:07Z","timestamp":1790787727635,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T00:00:00Z","timestamp":1660521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FARB2020"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sphingosine-1-phosphate (S1P) is involved in inflammatory signaling\/s associated with the development of respiratory disorders, including cancer. However, the underlying mechanism\/s are still elusive. The aim of this study was to investigate the role of S1P on circulating blood cells obtained from healthy volunteers and non-small cell lung cancer (NSCLC) patients. To pursue our goal, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with S1P. We found that the administration of S1P did not induce healthy PBMCs to release pro-inflammatory cytokines. In sharp contrast, S1P significantly increased the levels of TNF-\u03b1 and IL-6 from lung cancer-derived PBMCs. This effect was S1P receptor 3 (S1PR3)-dependent. The pharmacological blockade of ceramidase and sphingosine kinases (SPHKs), key enzymes for S1P synthesis, completely reduced the release of both TNF-\u03b1 and IL-6 after S1P addition on lung cancer-derived PBMCs. Interestingly, S1P-induced IL-6, but not TNF-\u03b1, release from lung cancer-derived PBMCs was mTOR- and K-Ras-dependent, while NF-\u03baB was not involved. These data identify S1P as a bioactive lipid mediator in a chronic inflammation-driven diseases such as NSCLC. In particular, the higher presence of S1P could orchestrate the cytokine milieu in NSCLC, highlighting S1P as a pro-tumor driver.<\/jats:p>","DOI":"10.3390\/cells11162524","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T03:33:20Z","timestamp":1660534400000},"page":"2524","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["S1P-Induced TNF-\u03b1 and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1871-7603","authenticated-orcid":false,"given":"Michela","family":"Terlizzi","sequence":"first","affiliation":[{"name":"Department of Pharmacy (DIFARMA), University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Colarusso","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFARMA), University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Somma","sequence":"additional","affiliation":[{"name":"Anatomy and Pathology Unit, Ospedale dei Colli, AORN, \u201cMonaldi\u201d, 84131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Anatomy and Pathology Unit, Ospedale dei Colli, AORN, \u201cMonaldi\u201d, 84131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Panico","sequence":"additional","affiliation":[{"name":"Anatomy and Pathology Unit, Ospedale dei Colli, AORN, \u201cMonaldi\u201d, 84131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFARMA), University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalinda","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFARMA), University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrm1103","article-title":"Sphingosine-1-phosphate: An enigmatic signalling lipid","volume":"4","author":"Spiegel","year":"2003","journal-title":"Nat. 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