{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:03:22Z","timestamp":1785427402137,"version":"3.56.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The circadian clock is closely associated with inflammatory reactions. Increased inflammatory cytokine levels have been detected in the airways of nocturnal asthma. However, the mechanisms that contribute to the nocturnal increase in inflammatory responses and the relationship with circadian clock remain unknown.<\/jats:p><jats:sec><jats:title>Methods<\/jats:title><jats:p>Inflammatory cytokine levels were measured in asthma patients with and without nocturnal symptoms. Allergic airway disease was induced in mice by ovalbumin (OVA), and different periods of light\/dark cycles were used to induce circadian rhythm disorders. Serum shock was used to stimulate the rhythmic expression in human bronchial epidermal cells (16HBE). The expression and oscillation of circadian clock genes and inflammatory cytokines in 16HBE cells subjected to brain and muscle ARNT-like protein-1 (BMAL1) and Forkhead Box A2 (FOXA2) knockdown and treatment with a FOXA2 overexpression plasmid were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Serum IL-6 was found to be significantly higher in asthmatic patients with nocturnal symptoms than those without nocturnal symptoms. The OVA-induced asthma model with a circadian rhythm disorder and 16HBE cells treated with serum shock showed an increase in IL-6 levels and a negative correlation with BMAL1 and FOXA2. The knockdown of BMAL1 resulted in a lower correlation between IL-6 and other rhythm clock genes. Furthermore, knockdown of the BMAL1 and FOXA2 in 16HBE cells reduced the expression and rhythmic fluctuations of IL-6.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggest that there are increased IL-6 levels in nocturnal asthma resulting from inhibition of the BMAL1\/FOXA2 signalling pathway in airway epithelial cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.947067","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T05:33:32Z","timestamp":1669354412000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["BMAL1\/FOXA2-induced rhythmic fluctuations in IL-6 contribute to nocturnal asthma attacks"],"prefix":"10.3389","volume":"13","author":[{"given":"Lingling","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaona","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolu","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1164\/rccm.202109-2205PP","article-title":"Global initiative for asthma strategy 2021: Executive summary and rationale for key changes","volume":"205","author":"Reddel","year":"2022","journal-title":"Am J Respir Crit Care Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.acap.2011.05.006","article-title":"Nocturnal asthma symptoms and poor sleep quality among urban school children with asthma","volume":"11","author":"Fagnano","year":"2011","journal-title":"Acad Pediatr"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1016\/j.jaci.2016.01.054","article-title":"Daily global stress is associated with nocturnal asthma awakenings in school-age children","volume":"138","author":"Horner","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3109\/02770909809048968","article-title":"Features that distinguish those who die from asthma from community controls with asthma","volume":"35","author":"Tough","year":"1998","journal-title":"J Asthma"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1097\/j.pbj.0000000000000040","article-title":"Thoracic fluid accumulation and asthma symptoms: A new contributor mechanism","volume":"4","author":"Francisco","year":"2019","journal-title":"Porto BioMed J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.02.00202002","article-title":"Increased alveolar nitric oxide concentration in asthmatic patients with nocturnal symptoms","volume":"20","author":"Lehtimaki","year":"2002","journal-title":"Eur Respir J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200202000-00011","article-title":"Circadian variation of exhaled nitric oxide and urinary eosinophil protein X in asthmatic and healthy children","volume":"51","author":"Mattes","year":"2002","journal-title":"Pediatr Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"897","DOI":"10.2147\/JAA.S313572","article-title":"The relevance of small airway dysfunction in asthma with nocturnal symptoms","volume":"14","author":"Abdo","year":"2021","journal-title":"J Asthma Allergy"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01387","article-title":"The intriguing role of interleukin 13 in the pathophysiology of asthma","volume":"10","author":"Marone","year":"2019","journal-title":"Front Pharmacol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1408886111","article-title":"A circadian gene expression atlas in mammals: implications for biology and medicine","volume":"111","author":"Zhang","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.52","article-title":"Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration","volume":"22","author":"Studer","year":"2015","journal-title":"Cell Death Differ"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbscr.2021.100063","article-title":"Night shift schedule alters endogenous regulation of circulating cytokines","volume":"10","author":"Liu","year":"2021","journal-title":"Neurobiol Sleep Circadian Rhythms"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2147\/JAA.S302508","article-title":"Disrupted expression of circadian clock genes in patients with bronchial asthma","volume":"14","author":"Chen","year":"2021","journal-title":"J Asthma Allergy"},{"key":"B14","unstructured":"Global strategy for asthma management and prevention2021"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201406-1130ED","article-title":"Understanding nocturnal asthma. the plot thickens","volume":"190","author":"Mehra","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.922003","article-title":"Qi-xian decoction upregulated e-cadherin expression in human lung epithelial cells and ovalbumin-challenged mice by inhibiting reactive oxygen species-mediated extracellular-Signal-Regulated kinase (ERK) activation","volume":"26","author":"Tang","year":"2020","journal-title":"Med Sci Monit"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e55398","DOI":"10.3791\/55398","article-title":"Bronchoalveolar lavage of murine lungs to analyze inflammatory cell infiltration","author":"Van Hoecke","year":"2017","journal-title":"J Vis Exp"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009097","article-title":"Diversified regulation of circadian clock gene expression following whole genome duplication","volume":"16","author":"West","year":"2020","journal-title":"PloS Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00769","article-title":"The adrenal clock prevents aberrant light-induced alterations in circadian glucocorticoid rhythms","volume":"159","author":"Engeland","year":"2018","journal-title":"Endocrinology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)81199-x","article-title":"A serum shock induces circadian gene expression in mammalian tissue culture cells","volume":"93","author":"Balsalobre","year":"1998","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-0610","article-title":"Evidence for circadian regulation of activating transcription factor 5 but not tyrosine hydroxylase by the chromaffin cell clock","volume":"148","author":"Lemos","year":"2007","journal-title":"Endocrinology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2013-203482","article-title":"The circadian clock and asthma","volume":"69","author":"Durrington","year":"2014","journal-title":"Thorax"},{"key":"B23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.4062\/biomolther.2020.215","article-title":"Cell autonomous circadian systems and their relation to inflammation","volume":"29","author":"Annamneedi","year":"2021","journal-title":"Biomol Ther (Seoul)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.700431","article-title":"The circadian clock protein BMAL1 acts as a metabolic sensor in macrophages to control the production of pro IL-1beta","volume":"12","author":"Timmons","year":"2021","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0122OC","article-title":"Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation","volume":"49","author":"Tang","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1210\/er.2013-1051","article-title":"The effects of light at night on circadian clocks and metabolism","volume":"35","author":"Fonken","year":"2014","journal-title":"Endocr Rev"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1530\/REP-09-0523","article-title":"Reproductive biology of female Bmal1 null mice","volume":"139","author":"Boden","year":"2010","journal-title":"Reproduction"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/srep12310","article-title":"Circadian and ultradian rhythms of clock gene expression in the suprachiasmatic nucleus of freely moving mice","volume":"5","author":"Ono","year":"2015","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1612917113","article-title":"Mammalian period represses and de-represses transcription by displacing CLOCK-BMAL1 from promoters in a cryptochrome-dependent manner","volume":"113","author":"Chiou","year":"2016","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2013.09.002","article-title":"Circadian aspects of energy metabolism and aging","volume":"12","author":"Froy","year":"2013","journal-title":"Ageing Res Rev"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s13105-015-0447-3","article-title":"Association between genetic variants of the clock gene and obesity and sleep duration","volume":"71","author":"Valladares","year":"2015","journal-title":"J Physiol Biochem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbih.2022.100428","article-title":"Disrupting circadian rhythms promotes cancer-induced inflammation in mice","volume":"21","author":"Lawther","year":"2022","journal-title":"Brain Behav Immun Health"},{"key":"B33","doi-asserted-by":"publisher","first-page":"4753","DOI":"10.1038\/ncomms5753","article-title":"Circadian rhythm reprogramming during lung inflammation","volume":"5","author":"Haspel","year":"2014","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00072.2017","article-title":"The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma","volume":"312","author":"Zaslona","year":"2017","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/mi.2017.24","article-title":"BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes","volume":"11","author":"Ehlers","year":"2018","journal-title":"Mucosal Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/1426846","article-title":"Effect of light-dark cycle misalignment on the hypothalamic-Pituitary-Gonadal axis, testicular oxidative stress, and expression of clock genes in adult Male rats","volume":"2020","author":"Moustafa","year":"2020","journal-title":"Int J Endocrinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3109\/07420528.2010.548615","article-title":"Hepatic, duodenal, and colonic circadian clocks differ in their persistence under conditions of constant light and in their entrainment by restricted feeding","volume":"28","author":"Polidarova","year":"2011","journal-title":"Chronobiol Int"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00152.2015","article-title":"Circadian molecular clock in lung pathophysiology","volume":"309","author":"Sundar","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-20-07525.2000","article-title":"Light and glutamate-induced degradation of the circadian oscillating protein BMAL1 during the mammalian clock resetting","volume":"20","author":"Tamaru","year":"2000","journal-title":"J Neurosci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.125133","article-title":"Bmal1 deletion in mice facilitates adaptation to disrupted light\/dark conditions","volume":"5","author":"Yang","year":"2019","journal-title":"JCI Insight"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/143.2.351","article-title":"Airways inflammation in nocturnal asthma","volume":"143","author":"Martin","year":"1991","journal-title":"Am Rev Respir Dis"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1136\/thx.49.3.257","article-title":"Role of inflammation in nocturnal asthma","volume":"49","author":"Mackay","year":"1994","journal-title":"Thorax"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/s0091-6749(95)70011-0","article-title":"Inflammatory cell number and mediators in bronchoalveolar lavage fluid and peripheral blood in subjects with asthma with increased nocturnal airways narrowing","volume":"96","author":"Oosterhoff","year":"1995","journal-title":"J Allergy Clin Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.770491","article-title":"Disrupted circadian rest-activity cycles in inflammatory bowel disease are associated with aggressive disease phenotype, subclinical inflammation, and dysbiosis","volume":"8","author":"Swanson","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"B45","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1002\/glia.23087","article-title":"The intrinsic microglial clock system regulates interleukin-6 expression","volume":"65","author":"Nakazato","year":"2017","journal-title":"Glia"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.71719","article-title":"BMAL1 regulates propionibacterium acnes-induced skin inflammation via REV-ERBalpha in mice","volume":"18","author":"Li","year":"2022","journal-title":"Int J Biol Sci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.712903","article-title":"Bmal1 downregulation worsens critical limb ischemia by promoting inflammation and impairing angiogenesis","volume":"8","author":"Xu","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200811-1768OC","article-title":"Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma","volume":"180","author":"Park","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000223","article-title":"Foxa2 programs Th2 cell-mediated innate immunity in the developing lung","volume":"184","author":"Chen","year":"2010","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2015.7.5.458","article-title":"Expression and regulation of transcription factor FoxA2 in chronic rhinosinusitis with and without nasal polyps","volume":"7","author":"Luo","year":"2015","journal-title":"Allergy Asthma Immunol Res"},{"key":"B51","article-title":"LncRNA-NEF regulated the hyperoxia-induced injury of lung epithelial cells by FOXA2","volume":"12","author":"Mei","year":"2020","journal-title":"Am J Transl Res"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00055","article-title":"Fine-tuning circadian rhythms: The importance of Bmal1 expression in the ventral forebrain","volume":"11","author":"Mieda","year":"2017","journal-title":"Front Neurosci"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201900535","article-title":"The molecular clock protein Bmal1 regulates cell differentiation in mouse embryonic stem cells","volume":"3","author":"Gallardo","year":"2020","journal-title":"Life Sci Alliance"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00058.2019","article-title":"BMAL1 controls glucose uptake through paired-homeodomain transcription factor 4 in differentiated caco-2 cells","volume":"317","author":"Sussman","year":"2019","journal-title":"Am J Physiol Cell Physiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.947067\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T05:33:42Z","timestamp":1669354422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.947067\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,25]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2022.947067"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.947067","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,25]]},"article-number":"947067"}}