{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:01:01Z","timestamp":1791928861852,"version":"4.3.4"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007951","name":"Tokyo Medical and Dental University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007951","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sekisui Chemical Co., Ltd.","award":["21BA110226"],"award-info":[{"award-number":["21BA110226"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Cold atmospheric plasma (CAP) has been studied and clinically applied to treat chronic wounds, cancer, periodontitis, and other diseases. CAP exerts cytotoxic, bactericidal, cell-proliferative, and anti-inflammatory effects on living tissues by generating reactive species. Therefore, CAP holds promise as a treatment for diseases involving chronic inflammation and bacterial infections. However, the cellular mechanisms underlying these anti-inflammatory effects of CAP are still unclear. Thus, this study aimed to elucidate the anti-inflammatory mechanisms of CAP <jats:italic>in vitro<\/jats:italic>. The human acute monocytic leukemia cell line, THP-1, was stimulated with lipopolysaccharide and irradiated with CAP, and the cytotoxic effects of CAP were evaluated. Time-course differentiation of gene expression was analyzed, and key transcription factors were identified via transcriptome analysis. Additionally, the nuclear localization of the CAP-induced transcription factor was examined using western blotting. The results indicated that CAP showed no cytotoxic effects after less than 70 s of irradiation and significantly inhibited interleukin 6 (<jats:italic>IL6<\/jats:italic>) expression after more than 40 s of irradiation. Transcriptome analysis revealed many differentially expressed genes (DEGs) following CAP irradiation at all time points. Cluster analysis classified the DEGs into four distinct groups, each with time-dependent characteristics. Gene ontology and gene set enrichment analyses revealed CAP-induced suppression of <jats:italic>IL6<\/jats:italic> production, other inflammatory responses, and the expression of genes related to major histocompatibility complex (MHC) class II. Transcription factor analysis suggested that nuclear factor erythroid 2-related factor 2 (NRF2), which suppresses intracellular oxidative stress, is the most activated transcription factor. Contrarily, regulatory factor X5, which regulates MHC class II expression, is the most suppressed transcription factor. Western blotting revealed the nuclear localization of NRF2 following CAP irradiation. These data suggest that CAP suppresses the inflammatory response, possibly by promoting NRF2 nuclear translocation.<\/jats:p>","DOI":"10.1371\/journal.pone.0292267","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T17:32:40Z","timestamp":1697650360000},"page":"e0292267","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Anti-inflammatory effects of cold atmospheric plasma irradiation on the THP-1 human acute monocytic leukemia cell line"],"prefix":"10.1371","volume":"18","author":[{"given":"Ito","family":"Hirasawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Odagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giri","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutvi","family":"Sanghavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaya","family":"Oshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Togi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsunori","family":"Yoshikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1610-7430","authenticated-orcid":true,"given":"Koji","family":"Mizutani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4193-219X","authenticated-orcid":true,"given":"Yasuo","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Katagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5936-1116","authenticated-orcid":true,"given":"Akira","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"pone.0292267.ref001","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.physrep.2013.05.005","article-title":"Plasmas for medicine","volume":"530","author":"T von Woedtke","year":"2013","journal-title":"Phys Rep"},{"key":"pone.0292267.ref002","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/ppap.200700154","article-title":"Applied plasma medicine","volume":"5","author":"G Fridman","year":"2008","journal-title":"Plasma Process Polym"},{"key":"pone.0292267.ref003","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3390\/plasma1010005","article-title":"Plasma medicine: A brief Introduction.","volume":"1","author":"M. 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in subgingival plaque.","volume":"25","author":"SS Socransky","year":"1998","journal-title":"J Clin Periodontol"},{"key":"pone.0292267.ref026","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1600-0757.2009.00333.x","article-title":"Contribution of Porphyromonas gingivalis lipopolysaccharide to periodontitis.","volume":"54","author":"S Jain","year":"2010","journal-title":"Periodontol 2000."},{"key":"pone.0292267.ref027","doi-asserted-by":"crossref","first-page":"e115107","DOI":"10.1371\/journal.pone.0115107","article-title":"Thrombospondin-1 production is enhanced by Porphyromonas gingivalis lipopolysaccharide in THP-1 cells.","volume":"9","author":"M Gokyu","year":"2014","journal-title":"PLoS One"},{"key":"pone.0292267.ref028","doi-asserted-by":"crossref","first-page":"e0161482","DOI":"10.1371\/journal.pone.0161482","article-title":"Effects of Porphyromonas gingivalis lipopolysaccharidetolerized monocytes on inflammatory responses in neutrophils.","volume":"11","author":"X-Q Zhu","year":"2016","journal-title":"PLoS One."},{"key":"pone.0292267.ref029","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1177\/1753425907088244","article-title":"Lipopolysaccharide (LPS) of Porphyromonas gingivalis induces IL-1\u03b2, TNF-\u03b1 and IL-6 production by THP-1 cells in a way different from that of Escherichia coli LPS.","volume":"14","author":"D Zhang","year":"2008","journal-title":"Innate Immun."},{"key":"pone.0292267.ref030","doi-asserted-by":"crossref","first-page":"7611","DOI":"10.1074\/jbc.274.12.7611","article-title":"Bacterial lipopolysaccharide activates nuclear factor-\u03baB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes*","volume":"274","author":"FX Zhang","year":"1999","journal-title":"J Biol Chem"},{"key":"pone.0292267.ref031","doi-asserted-by":"crossref","first-page":"6185","DOI":"10.4049\/jimmunol.172.10.6185","article-title":"Lipopolysaccharide-binding protein critically regulates lipopolysaccharide-induced IFN-beta signaling pathway in human monocytes","volume":"172","author":"A Kato","year":"2004","journal-title":"J Immunol"},{"key":"pone.0292267.ref032","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/jre.12733","article-title":"Inflammasomes and their regulation in periodontal disease: A review.","volume":"55","author":"K Aral","year":"2020","journal-title":"J Periodontal Res"},{"key":"pone.0292267.ref033","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1089\/ars.2015.6256","article-title":"Nitrate\/Nitrite as Critical Mediators to Limit Oxidative Injury and Inflammation","volume":"23","author":"P Waltz","year":"2015","journal-title":"Antioxid Redox 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functions","volume":"2012","author":"RV Luckheeram","year":"2012","journal-title":"Clin Dev Immunol"},{"key":"pone.0292267.ref038","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/omi.12144","article-title":"T cells, teeth and tissue destruction\u2014what do T cells do in periodontal disease?","volume":"31","author":"L Campbell","year":"2016","journal-title":"Mol Oral Microbiol"},{"key":"pone.0292267.ref039","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1034\/j.1600-051X.2002.290807.x","article-title":"Some cytokine profiles of T-helper cells in lesions of advanced periodontitis","volume":"29","author":"T Berglundh","year":"2002","journal-title":"J Clin Periodontol"},{"key":"pone.0292267.ref040","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/imm.13280","article-title":"Cytokine-regulated Th17 plasticity in human health and diseases","volume":"163","author":"S Cerboni","year":"2021","journal-title":"Immunology"},{"key":"pone.0292267.ref041","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2174\/187152812800392805","article-title":"The IL23\/Th17 pathway as a therapeutic target in chronic inflammatory diseases","volume":"11","author":"E. 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