{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T02:47:56Z","timestamp":1772592476785,"version":"3.50.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Exposure to environmental hormones such as di(2-ethylhexyl) phthalate (DEHP) has become a critical human health issue globally. This study aimed to investigate the correlations between DEHP\/mono-(2-ethylhexyl) phthalate (MEHP) levels and macrophage-associated immune responses and clinical manifestations in dengue virus (DV)-infected patients. Among 89 DV-infected patients, those with DV infection-related gastrointestinal (GI) bleeding (n = 13, 15% of patients) had significantly higher DEHP exposure than those without GI bleeding (n = 76, 85% of patients), which were 114.2 ng\/ml versus 52.5 ng\/ml \u03a3DEHP in urine; p = 0.023). In an<jats:italic>in vitro<\/jats:italic>study using cultured human monocyte-derived macrophages (MDMs) to investigate the effects of MEHP, treatment increased IL-1\u03b2 and TNF-\u03b1 release but decreased IL-23 release, with negative correlations observed between urine \u03a3DEHP and serum IL-23 levels in patients. MEHP-treated MDMs had lower antiviral Th17 response induction activity in mixed T-cell response tests. The<jats:italic>in vitro<\/jats:italic>data showed that MEHP increased DV viral load and decreased IL-23 release dose-dependently, and adding IL-23 to MEHP-exposed MDMs significantly reduced the DV viral load. MEHP also suppressed IL-23 expression<jats:italic>via<\/jats:italic>the peroxisome proliferator-activated receptor-gamma (PPAR-\u03b3) pathway. Further, the PPAR-\u03b3 antagonist GW9662 significantly reversed MEHP-induced IL-23 suppression and reduced the DV viral load. These study findings help to explain the associations between high MEHP levels and the high global burden of dengue disease.<\/jats:p>","DOI":"10.3389\/fimmu.2021.599345","type":"journal-article","created":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T14:39:13Z","timestamp":1613486353000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Mono-(2-ethylhexyl) phthalate Promotes Dengue Virus Infection by Decreasing IL-23-Mediated Antiviral Responses"],"prefix":"10.3389","volume":"12","author":[{"given":"Chun-Yu","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Hao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Hung","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyrki","family":"Tenhunen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling-Chien","family":"Hung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Chou","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Cheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Hsu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Ting","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"B1","article-title":"WHO Guidelines Approved by the Guidelines Review Committee","volume-title":"Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition","year":"2009"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.coviro.2020.06.008","article-title":"Risk factors and biomarkers of severe dengue","volume":"43","author":"Rathore","year":"2020","journal-title":"Curr Opin Virol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe1413146","article-title":"Preventing dengue\u2013is the possibility now a reality","volume":"372","author":"Thomas","year":"2015","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.09.014","article-title":"High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity","volume":"48","author":"Lin","year":"2019","journal-title":"EBioMedicine"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2016.124","article-title":"Consecutive large dengue outbreaks in Taiwan in 2014-2015","volume":"5","author":"Wang","year":"2016","journal-title":"Emerg Microbes Infect"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.358.6370.1514","article-title":"Safety concerns derail dengue vaccination program","volume":"358","author":"Normile","year":"2017","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120083","article-title":"Influence of phthalates on cytokine production in monocytes and macrophages: a systematic review of experimental trials","volume":"10","author":"Hansen","year":"2015","journal-title":"PloS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s12929-015-0191-6","article-title":"Biomarkers of severe dengue disease - a review","volume":"22","author":"John","year":"2015","journal-title":"J BioMed Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/srep45009","article-title":"Estimated Daily Intake and Cumulative Risk Assessment of Phthalates in the General Taiwanese after the 2011 DEHP Food Scandal","volume":"7","author":"Chang","year":"2017","journal-title":"Sci Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5173(98)00411-6","article-title":"Exposure of hemodialysis patients to di-2-ethylhexyl phthalate","volume":"180","author":"Faouzi","year":"1999","journal-title":"Int J Pharm"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0208081","article-title":"Percentage fractions of urinary di(2-ethylhexyl) phthalate metabolites: Association with obesity and insulin resistance in Korean girls","volume":"13","author":"Kim","year":"2018","journal-title":"PloS One"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2011.12.002","article-title":"3rd. In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat","volume":"26","author":"Choi","year":"2012","journal-title":"Toxicol In Vitro"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2007.00837.x","article-title":"Phthalates: metabolism and exposure","volume":"31","author":"Wittassek","year":"2008","journal-title":"Int J Androl"},{"key":"B14","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.toxlet.2011.11.016","article-title":"Mono-2-ethylhexylphthalate (MEHP) induces TNF-alpha release and macrophage differentiation through different signalling pathways in RAW264.7 cells","volume":"209","author":"Bolling","year":"2012","journal-title":"Toxicol Lett"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01568-07","article-title":"Primary human splenic macrophages, but not T or B cells, are the principal target cells for dengue virus infection in vitro","volume":"81","author":"Blackley","year":"2007","journal-title":"J Virol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12929-018-0482-9","article-title":"The monocyte-macrophage-mast cell axis in dengue pathogenesis","volume":"25","author":"Wan","year":"2018","journal-title":"J BioMed Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01426","article-title":"IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis","volume":"10","author":"Fahey","year":"2019","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal5088","article-title":"Increased adaptive immune responses and proper feedback regulation protect against clinical dengue","volume":"9","author":"Simon-Loriere","year":"2017","journal-title":"Sci Transl Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60572-9","article-title":"Dengue","volume":"385","author":"Guzman","year":"2015","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/1423-0127-20-36","article-title":"Distinct regulation of dengue virus-induced inflammasome activation in human macrophage subsets","volume":"20","author":"Wu","year":"2013","journal-title":"J BioMed Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.07.007","article-title":"Caspase-1-processed IL-1 family cytokines play a vital role in driving innate IL-17","volume":"56","author":"Dungan","year":"2011","journal-title":"Cytokine"},{"key":"B22","doi-asserted-by":"publisher","first-page":"57","DOI":"10.5491\/SHAW.2011.2.1.57","article-title":"Determination of Phthalate Metabolites in Human Serum and Urine as Biomarkers for Phthalate Exposure Using Column-Switching LC-MS\/MS","volume":"2","author":"Jeong","year":"2011","journal-title":"Saf Health Work."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2018.11.043","article-title":"Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid","volume":"123","author":"Martinez","year":"2019","journal-title":"Environ Int"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122637","article-title":"Lipopolysaccharide-Induced Nitric Oxide, Prostaglandin E2, and Cytokine Production of Mouse and Human Macrophages Are Suppressed by Pheophytin-b","volume":"18","author":"Lin","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.3.1904","article-title":"Peroxisome proliferator-activated receptor-gamma agonists suppress the production of IL-12 family cytokines by activated glia","volume":"178","author":"Xu","year":"2007","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"27003","DOI":"10.1289\/EHP3730","article-title":"The Role of Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation","volume":"127","author":"Shoaito","year":"2019","journal-title":"Environ Health Perspect"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/jcm7110396","article-title":"Prognostic Factors in Adult Patients with Dengue: Developing Risk Scoring Models and Emphasizing Factors Associated with Death \u22647 Days after Illness Onset and \u22643 Days after Presentation","volume":"7","author":"Lee","year":"2018","journal-title":"J Clin Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00035-09","article-title":"Dengue virus pathogenesis: an integrated view","volume":"22","author":"Martina","year":"2009","journal-title":"Clin Microbiol Rev"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006673","article-title":"Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components","volume":"13","author":"Glasner","year":"2017","journal-title":"PloS Pathog"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007033","article-title":"Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability","volume":"14","author":"Chen","year":"2018","journal-title":"PloS Pathog"},{"key":"B31","doi-asserted-by":"crossref","first-page":"67.5","DOI":"10.4049\/jimmunol.188.Supp.67.5","article-title":"Inflammatory macrophages in dengue virus infection pyroptosis, infectivity, and enhancement of endothelial permeability","volume":"188","author":"Hsieh","year":"2012","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1690","article-title":"Prospects for a dengue virus vaccine","volume":"5","author":"Whitehead","year":"2007","journal-title":"Nat Rev Microbiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2018.12.024","article-title":"Inflammasome activation and Th17 responses","volume":"107","author":"Deng","year":"2019","journal-title":"Mol Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316830","article-title":"IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes","volume":"69","author":"Sun","year":"2019","journal-title":"Gut"},{"key":"B35","doi-asserted-by":"publisher","first-page":"5310","DOI":"10.1038\/s41598-019-41655-7","article-title":"Monocytes\/Macrophages play a pathogenic role in IL-23 mediated psoriasis-like skin inflammation","volume":"9","author":"Wang","year":"2019","journal-title":"Sci Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.599345\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T08:34:44Z","timestamp":1697877284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.599345\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,15]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2021.599345"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.599345","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,15]]},"article-number":"599345"}}