{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:30:27Z","timestamp":1791304227144,"version":"4.3.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"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:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The transcription factor NF-\u03baB is a central regulator of immune and inflammatory responses whose activity is tightly controlled by I\u03baB proteins and glucocorticoid receptor (GR)-mediated repression. However, the diversity of NF-\u03baB subunit variants and their contribution to glucocorticoid signaling remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human peripheral blood mononuclear cells (PBMCs) exposed to pro- and anti-inflammatory stimuli were analyzed to identify splice variants of the NF-\u03baB subunit p65 iso5. mRNA expression was evaluated under different stimuli. Protein interactions with the synthetic glucocorticoid dexamethasone (Dex) and GR were assessed, together with nuclear translocation dynamics. Functional transcriptional activity was examined using NF-\u03baB and IL-2 responsive promoter assays. Expression profiling was also performed in disease contexts, including COVID-19 and liver cirrhosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified and characterized two previously unrecognized splice variants of p65 iso5, named p65 iso5 \u03946\/7 and p65 iso5 \u039410. Their mRNA expression was differentially regulated depending on the stimulus. Both isoforms unexpectedly bound dexamethasone, formed nuclear complexes with Dex-activated GR, and translocated to the nucleus independently of I\u03baB\u03b1. Functional assays revealed distinct transcriptional activities on NF-\u03baB and IL-2 responsive promoters, indicating that these isoforms act as noncanonical modulators of glucocorticoid signaling. Expression profiling showed disease-specific regulation, with reciprocal modulation of the two isoforms in COVID-19 and selective upregulation of p65 iso5 \u03946\/7 in liver cirrhosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings uncover a previously unrecognized layer of NF-\u03baB\/GR crosstalk and identify a new class of dexamethasone-binding proteins outside the nuclear receptor superfamily. Our data highlight their glucocorticoid-interacting properties and provide mechanistic insight into the diversity of glucocorticoid responses, with potential implications for inflammation-related pathologies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1748334","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:22:56Z","timestamp":1773750176000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["New p65 iso5 isoforms as dexamethasone-binding proteins: novel potential therapeutic targets for inflammatory diseases"],"prefix":"10.3389","volume":"17","author":[{"given":"Gaetano","family":"Spinelli","sequence":"first","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppa","family":"Biddeci","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioacchin","family":"Iannolo","sequence":"additional","affiliation":[{"name":"Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico and Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione (IRCCS)","place":["Palermo, Italy"]},{"name":"Department of Medicine and Surgery, Universit\u00e0 degli Studi di Enna \u201cKore\u201d","place":["Enna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Colomba","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Duro","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela Maria","family":"Marsana","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso Silvano","family":"Aronica","sequence":"additional","affiliation":[{"name":"Complex Operative Unit of Clinical Pathology, Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico Di Cristina e Benfratelli Hospitals","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Di Blasi","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2011.13","article-title":"NF-\u03baB in Immunobiology","volume":"21","author":"Hayden","year":"2011","journal-title":"Cell Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"153712","DOI":"10.1016\/j.phymed.2021.153712","article-title":"Cascade of immune mechanism and consequences of inflammatory disorders","volume":"91","author":"Megha","year":"2021","journal-title":"Phytomedicine"},{"key":"B4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s00005-011-0136-z","article-title":"Nuclear factor-\u03baB: a key regulator in health and disease of lungs","volume":"59","author":"Batra","year":"2011","journal-title":"Archivum Immunologiae Therapiae Experimentalis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1101\/gad.183434.111","article-title":"NF-\u03baB, the first quarter-century: remarkable progress and outstanding questions","volume":"26","author":"Hayden","year":"2012","journal-title":"Genes Dev"},{"key":"B6","doi-asserted-by":"publisher","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduction Targeted Ther"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2006.00375.x","article-title":"Circuitry of nuclear factor kappaB signaling","volume":"210","author":"Hoffmann","year":"2006","journal-title":"Immunol Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209933","article-title":"Transcriptional regulation via the NF-kappaB signaling module","volume":"25","author":"Hoffmann","year":"2006","journal-title":"Oncogene"},{"key":"B9","doi-asserted-by":"publisher","first-page":"a000034","DOI":"10.1101\/cshperspect.a000034","article-title":"The NF-kappaB family of transcription factors and its regulation","volume":"1","author":"Oeckinghaus","year":"2009","journal-title":"Cold Spring Harbor Perspect Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/ni.2151","article-title":"Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-\u03baB family DNA binding","volume":"13","author":"Siggers","year":"2011","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/j.1600-065X.2012.01097.x","article-title":"NF-\u03baB regulation: lessons from structures","volume":"246","author":"Ghosh","year":"2012","journal-title":"Immunol Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.52","article-title":"The non-canonical NF-\u03baB pathway in immunity and inflammation","volume":"17","author":"Sun","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41392-024-01757-9","article-title":"NF-\u03baB in biology and targeted therapy: new insights and translational implications","volume":"9","author":"Guo","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B14","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/cr.2010.161","article-title":"A single NF\u03baB system for both canonical and non-canonical signaling","volume":"21","author":"Shih","year":"2011","journal-title":"Cell Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.07.004","article-title":"Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma","volume":"12","author":"Annunziata","year":"2007","journal-title":"Cancer Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.immuni.2008.01.009","article-title":"TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor","volume":"28","author":"Gardam","year":"2008","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.07.003","article-title":"Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma","volume":"12","author":"Keats","year":"2007","journal-title":"Cancer Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/cr.2010.177","article-title":"Non-canonical NF-\u03baB signaling pathway","volume":"21","author":"Sun","year":"2011","journal-title":"Cell Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-kappaB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes Dev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.22.2723","article-title":"Rel\/NF-kappa B\/I kappa B family: intimate tales of association and dissociation","volume":"9","author":"Verma","year":"1995","journal-title":"Genes Dev"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90320-X","article-title":"DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide","volume":"64","author":"Nolan","year":"1991","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1101\/gad.4.11.1975","article-title":"The 65-kD subunit of NF-kappa B is a receptor for I kappa B and a modulator of DNA-binding specificity","volume":"4","author":"Urban","year":"1990","journal-title":"Genes Dev"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3390\/cells5010012","article-title":"The regulation of NF-\u03baB subunits by phosphorylation","volume":"18","author":"Christian","year":"2016","journal-title":"Cells Mar"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2015.03.053","article-title":"The nuclear I\u03baB family of proteins controls gene regulation and immune homeostasis","volume":"28","author":"Maruyama","year":"2015","journal-title":"Int Immunopharmacol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s44466-025-00014-0","article-title":"NF-\u03baB: master regulator of cellular responses in health and disease","volume":"1","author":"Hoffmann","year":"2025","journal-title":"Immun Inflammation"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.104","article-title":"NF-\u03baB signaling in inflammation and cancer","volume":"2","author":"Zhang","year":"2021","journal-title":"MedComm"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.02.033","article-title":"Crosstalk between NFkB and glucocorticoid signaling: A potential target of breast cancer therapy","volume":"322","author":"Ling","year":"2012","journal-title":"Cancer Lett"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2015.04.007","article-title":"Specificity and sensitivity of glucocorticoid signaling in health and disease","volume":"29","author":"Cain","year":"2015","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021909-135917","article-title":"Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics","volume":"72","author":"Huang","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-540-38918-7_66","article-title":"Gluco-\/mineralocorticoid receptors","volume-title":"Encyclopedia of molecular pharmacology","author":"Reichardt","year":"2008"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01545","article-title":"A general introduction to glucocorticoid biology","volume":"10","author":"Timmermans","year":"2019","journal-title":"Front Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.3390\/cells12121636","article-title":"The biologist\u2019s guide to the glucocorticoid receptor\u2019s structure","volume":"12","author":"Deploey","year":"2023","journal-title":"Cells"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI88886","article-title":"Glucocorticoid receptors: finding the middle ground","volume":"127","author":"Desmet","year":"2017","journal-title":"J Clin Invest"},{"key":"B34","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1677\/jme.0.0280069","article-title":"Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids","volume":"28","author":"Almawi","year":"2002","journal-title":"J Mol Endocrinol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0013","article-title":"Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases","volume":"30","author":"Beck","year":"2009","journal-title":"Endocrine Rev"},{"key":"B36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1128\/MMBR.00064-15","article-title":"The interactome of the glucocorticoid receptor and its influence on the actions of glucocorticoids in combatting inflammatory and infectious diseases","volume":"80","author":"Petta","year":"2016","journal-title":"Microbiol Mol Biol Reviews: MMBR"},{"key":"B37","doi-asserted-by":"publisher","first-page":"100741","DOI":"10.1016\/j.mcpro.2024.100741","article-title":"Selective modulation of the human glucocorticoid receptor compromises GR chromatin occupancy and recruitment of p300\/CBP and the mediator complex","volume":"23","author":"Van Moortel","year":"2024","journal-title":"Mol Cell Proteomics"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(94)90823-0","article-title":"An alternatively spliced transcript, p65 delta 2, of the gene encoding the p65 subunit of the transcription factor NF-kappa B","volume":"138","author":"Lyle","year":"1994","journal-title":"Gene"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(95)00578-1","article-title":"A novel NF-kappa B p65 spliced transcript lacking exons 6 and 7 in a non-small cell lung carcinoma cell line","volume":"166","author":"Maxwell","year":"1995","journal-title":"Gene"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.256.5055.367","article-title":"Identification of a naturally occurring transforming variant of the p65 subunit of NF-kappa B","volume":"256","author":"Narayanan","year":"1992","journal-title":"Sci (New York NY)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/cells14030230","article-title":"Fabry Disease and Inflammation: Potential Role of p65 iso5, an Isoform of the NF-\u03baB Complex","volume":"6","author":"Biddeci","year":"2025","journal-title":"Cells"},{"key":"B42","doi-asserted-by":"publisher","first-page":"22913","DOI":"10.1038\/s41598-021-02119-z","article-title":"A new p65 isoform that bind the glucocorticoid hormone and is expressed in inflammation liver diseases and COVID-19","volume":"11","author":"Spinelli","year":"2021","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1038\/s41467-018-03780-1","article-title":"Cryptic glucocorticoid receptor-binding sites pervade genomic NF-\u03baB response elements","volume":"9","author":"Hudson","year":"2018","journal-title":"Nat Commun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.220413297","article-title":"Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-\u03baB and the glucocorticoid receptor","volume":"97","author":"Doucas","year":"2000","journal-title":"Proceedings of the National Academy of Sciences of the United States of America (PNAS)"},{"key":"B45","doi-asserted-by":"publisher","first-page":"R108","DOI":"10.1186\/ar2763","article-title":"Flow cytometry analysis of glucocorticoid receptor expression and binding in steroid-sensitive and steroid-resistant patients with systemic lupus erythematosus","volume":"11","author":"Du","year":"2009","journal-title":"Arthritis Res Ther"},{"key":"B46","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.jneuroim.2013.04.024","article-title":"Dexamethasone-FITC staining application for measurement of circadian rhythmicity of glucocorticoid receptor expression in mouse living thymocyte subsets","volume":"261","author":"Kowalik","year":"2013","journal-title":"J Neuroimmunology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1016\/j.molcel.2025.03.004","article-title":"Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms","volume":"85","author":"Lambourne","year":"2024","journal-title":"bioRxiv: Preprint Server For Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01310-w","article-title":"NF-\u03baB in inflammation and cancer","volume":"22","author":"Mao","year":"2025","journal-title":"Cell Mol Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.20.4.0375","article-title":"Molecular control of immune\/inflammatory responses: interactions between nuclear factor-\u03baB and steroid receptor-signaling pathways","volume":"20","author":"McKay","year":"1999","journal-title":"Endocrine Rev"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00490-8","article-title":"Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65\/RelA","volume":"12","author":"Ryo","year":"2003","journal-title":"Mol Cell"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg139","article-title":"Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1)","volume":"22","author":"Vermeulen","year":"2003","journal-title":"EMBO J"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.11.036","article-title":"RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias","volume":"141","author":"Comrie","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.02.001","article-title":"Interleukin-2 signaling in the regulation of T cell biology in autoimmunity and cancer","volume":"57","author":"Shouse","year":"2024","journal-title":"Immunity"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1038\/s41467-022-28846-z","article-title":"Differential recognition of canonical NF-\u03baB dimers by Importin \u03b13","volume":"13","author":"Florio","year":"2022","journal-title":"Nat Commun"},{"key":"B55","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1210\/er.2002-0006","article-title":"The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression","volume":"24","author":"De Bosscher","year":"2003","journal-title":"Endocrine Rev"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1748334\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:22:57Z","timestamp":1773750177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1748334\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,17]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2026.1748334"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1748334","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,17]]},"article-number":"1748334"}}