{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:00:13Z","timestamp":1785214813445,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Animal studies suggest that post-stroke inflammatory responses are sexually dimorphic and may influence recovery. We examined whether men and women with acute ischemic stroke differ in ex vivo cytokine synthesis and whether such differences relate to functional outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We included 279 patients with acute ischemic stroke (mean age: 68.5\u00a0\u00b1\u00a012.8; 41.2% women). Blood samples collected on day 3 after stroke were stimulated with lipopolysaccharide (LPS). Ex vivo production of TNF\u03b1, IP-10, IL-1\u03b2, IL-6, IL-8, IL-10, and IL-12p70 was measured using enzyme-linked immunoassay or cytometric methods, and expression of LPS-induced cytokine and chemokine genes was assessed by RNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Greater stroke severity, lower monocyte counts, and the use of angiotensin receptor blockers were associated with decreased production of pro-inflammatory cytokines. Compared with females, males showed higher ex vivo synthesis of TNF\u03b1 (mean: 2814.2 vs 2302.7 pg\/mL, P\u00a0=\u00a00.003), IL-1\u03b2 (1851.9 vs 1461.3 pg\/mL, P\u00a0=\u00a00.002), IL-6 (14345.3 vs 11846.5 pg\/mL, P\u00a0=\u00a00.004), IL-12 (7.1 vs 4.2 pg\/mL, P\u00a0=\u00a00.002), and IP-10 (557.9 vs 435.1 pg\/mL, P\u00a0=\u00a00.038), with correspondingly higher gene expression levels of TNF\u03b1, IL-1\u03b2, IL-6, and IL-12. In multivariable quantile regression models adjusted for cytokine-specific covariates, male sex remained significantly associated with higher levels of TNF\u03b1, IL-1\u03b2, and IL-6. Despite this sex-related difference in inflammatory response, three-month functional outcomes were similar in men and women.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Males exhibited greater ex vivo pro-inflammatory cytokine production after ischemic stroke, but this sexual dimorphism did not translate into differences in functional recovery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1856274","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:26:49Z","timestamp":1785212809000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex differences in ex vivo cytokine production and their association with outcome following ischemic stroke"],"prefix":"10.3389","volume":"17","author":[{"given":"Marcin","family":"Piechota","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacogenomics, Maj Institute of Pharmacology, Polish Academy of Sciences","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Korostynski","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacogenomics, Maj Institute of Pharmacology, Polish Academy of Sciences","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazimierz","family":"Weglarczyk","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Siedlar","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Dziedzic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jagiellonian University Medical College","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI135530","article-title":"Immune responses to stroke: mechanisms, modulation, and therapeutic potential","volume":"130","author":"Iadecola","year":"2020","journal-title":"J Clin Invest"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105836","article-title":"Sexual dimorphism in immune cell responses following stroke","volume":"172","author":"Liu","year":"2022","journal-title":"Neurobiol Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.122.036945","article-title":"Sex-specific immune responses in stroke","volume":"53","author":"Banerjee","year":"2022","journal-title":"Stroke"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.02.001","article-title":"Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice","volume":"87","author":"Ahnstedt","year":"2020","journal-title":"Brain Behav Immun"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-013-0268-z","article-title":"Phenotypic changes in immune cell subsets reflect increased infarct volume in male vs. female mice","volume":"4","author":"Banerjee","year":"2013","journal-title":"Transl Stroke Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cellimm.2017.06.003","article-title":"Sex differences in regulatory cells in experimental stroke","volume":"318","author":"Seifert","year":"2017","journal-title":"Cell Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2020\/8880244","article-title":"The poststroke peripheral immune response is differentially regulated by leukemia inhibitory factor in aged male and female rodents","volume":"2020","author":"Davis","year":"2020","journal-title":"Oxid Med Cell Longev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2014.11.020","article-title":"Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke","volume":"278","author":"Dotson","year":"2015","journal-title":"J Neuroimmunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.3","article-title":"Sex differences in minocycline-induced neuroprotection after experimental stroke","volume":"29","author":"Li","year":"2009","journal-title":"J Cereb Blood Flow Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.629337","article-title":"The X-chromosome has a different pattern of gene expression in women compared with men with ischemic stroke","volume":"43","author":"Stamova","year":"2012","journal-title":"Stroke"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.179","article-title":"Effects of gender on gene expression in the blood of ischemic stroke patients","volume":"32","author":"Tian","year":"2012","journal-title":"J Cereb Blood Flow Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0102550","article-title":"Gene expression in peripheral immune cells following cardioembolic stroke is sexually dimorphic","volume":"9","author":"Stamova","year":"2014","journal-title":"PloS One"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202350519","article-title":"Whole blood stimulation as a tool for studying the human immune system","volume":"54","author":"M\u00fcller","year":"2024","journal-title":"Eur J Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12979-023-00383-3","article-title":"Toll-like receptor 4 (TLR4): new insight immune and aging","volume":"20","author":"Kim","year":"2023","journal-title":"Immun Ageing"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.12.015","article-title":"Reduced release of TNF\u03b1 and IP-10 after ex vivo blood stimulation with endotoxin is associated with poor outcome after stroke","volume":"102","author":"Klimiec","year":"2018","journal-title":"Cytokine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s12974-018-1156-y","article-title":"Reduced ex vivo release of pro-inflammatory cytokines and elevated plasma interleukin-6 are inflammatory signatures of post-stroke delirium","volume":"15","author":"Kowalska","year":"2018","journal-title":"J Neuroinflamm"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-019-1691-1","article-title":"The specific ex vivo released cytokine profile is associated with ischemic stroke outcome and improves its prediction","volume":"17","author":"Klimiec-Moskal","year":"2020","journal-title":"J Neuroinflamm"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2020.07.035","article-title":"Ex vivo synthesized cytokines as a biomarker of stroke-associated pneumonia","volume":"510","author":"Gradek-Kwinta","year":"2020","journal-title":"Clin Chim Acta"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychores.2023.111426","article-title":"Reduced ex vivo TNF\u03b1 synthesis upon whole blood stimulation with endotoxin predicts post-stroke fatigue","volume":"172","author":"Koceniak","year":"2023","journal-title":"J Psychosom Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41398-021-01359-x","article-title":"Toll-like receptor 4-mediated cytokine synthesis and post-stroke depressive symptoms","volume":"11","author":"Korostynski","year":"2021","journal-title":"Transl Psychiatry"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15902","article-title":"Gene expression profiling in whole blood stimulated ex vivo with lipopolysaccharide as a tool to predict post\u2010stroke depressive symptoms: Proof\u2010of\u2010concept study","volume":"166","author":"Piechota","year":"2023","journal-title":"J Neurochem"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000004017","article-title":"Quantile regression and its applications: a primer for anesthesiologists","volume":"128","author":"Staffa","year":"2019","journal-title":"Anesth Analg"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v96.7.2584.h8002584_2584_2591","article-title":"Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE","volume":"96","author":"Suzuki","year":"2000","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.4.2570","article-title":"Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity","volume":"175","author":"Wurfel","year":"2005","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature03985","article-title":"A network-based analysis of systemic inflammation in humans","volume":"437","author":"Calvano","year":"2005","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/j.cell.2016.10.018","article-title":"Host and environmental factors influencing individual human cytokine responses","volume":"167","author":"Ter Horst","year":"2016","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200201)46:13C250::AID-ART100643E3.0.CO;2-T","article-title":"Sexual dimorphism in innate immunity","volume":"46","author":"Moxley","year":"2002","journal-title":"Arthritis Rheum"},{"key":"B28","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.jri.2006.01.004","article-title":"Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages: a possible mechanism for gender-based differences in endotoxic shock susceptibility","volume":"71","author":"Marriott","year":"2006","journal-title":"J Reprod Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2023.1660","article-title":"Safety and efficacy of ApTOLL in patients with ischemic stroke undergoing endovascular treatment: a phase 1\/2 randomized clinical trial","volume":"80","author":"Hern\u00e1ndez-Jim\u00e9nez","year":"2023","journal-title":"JAMA Neurol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000005602","article-title":"Factors contributing to sex differences in functional outcomes and participation after stroke","volume":"90","author":"Phan","year":"2018","journal-title":"Neurology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207346","article-title":"Biological mechanism of sex difference in stroke manifestation and outcomes","volume":"100","author":"Ryu","year":"2023","journal-title":"Neurology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2377-7-5","article-title":"Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production","volume":"7","author":"Emsley","year":"2007","journal-title":"BMC Neurol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.jim.2008.10.005","article-title":"Whole-blood culture is a valid low-cost method to measure monocytic cytokines - a comparison of cytokine production in cultures of human whole-blood, mononuclear cells and monocytes","volume":"340","author":"Damsgaard","year":"2009","journal-title":"J Immunol Methods"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031772","article-title":"Immunomodulatory activity of the most commonly used antihypertensive drugs-angiotensin converting enzyme inhibitors and angiotensin II receptor blockers","volume":"23","author":"Bryniarski","year":"2022","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1856274\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:26:51Z","timestamp":1785212811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1856274\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2026.1856274"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1856274","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"article-number":"1856274"}}