{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:55:25Z","timestamp":1790315725693,"version":"4.1.0"},"reference-count":40,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2019,8,28]],"date-time":"2019-08-28T00:00:00Z","timestamp":1566950400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2017M620380"],"award-info":[{"award-number":["2017M620380"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012151","name":"sanming project of medicine in shenzhen","doi-asserted-by":"publisher","award":["SZSM 201512036"],"award-info":[{"award-number":["SZSM 201512036"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basic Research Program of Shenzhen Innovation Council of China","award":["JCYJ20170306161518559"],"award-info":[{"award-number":["JCYJ20170306161518559"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81800993"],"award-info":[{"award-number":["81800993"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Natural Science Foundation of Guangdong Province of China","award":["2017A030310599"],"award-info":[{"award-number":["2017A030310599"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:p>IgG4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic fibroinflammatory disease that affects salivary glands and leads to hyposalivation. Tumor necrosis factor\u2013\u03b1 (TNF-\u03b1) is a critical proinflammatory cytokine involved in several salivary gland disorders, but its role and mechanism regarding acinar cell injury in IgG4-RS are unknown. Here, we found that TNF-\u03b1 level was significantly increased in serum and submandibular gland (SMG) of patients and that serum TNF-\u03b1 level was negatively correlated with saliva flow rate. Ultrastructural observations of IgG4-RS SMGs revealed accumulation of large autophagic vacuoles, as well as dense fibrous bundles, decreased secretory granules, widened intercellular spaces, swollen mitochondria, and expanded endoplasmic reticulum. Expression levels of LC3 and p62 were both increased in patients\u2019 SMGs. TNF-\u03b1 treatment led to elevated levels of LC3II and p62 in both SMG-C6 cells and cultured human SMG tissues but did not further increase their levels when combined with bafilomycin A1 treatment. Moreover, transfection of Ad-mCherry-GFP-LC3B in SMG-C6 cells confirmed the suppression of autophagic flux after TNF-\u03b1 treatment. Immunofluorescence imaging revealed that costaining of LC3 and the lysosomal marker LAMP2 was significantly decreased in patients, TNF-\u03b1\u2013treated SMG-C6 cells, and cultured human SMGs, indicating a reduction in autophagosome-lysosome fusion. Furthermore, the ratio of pro\/mature cathepsin D was elevated in vivo, ex vivo, and in vitro. TNF-\u03b1 also appeared to induce abnormal acidification of lysosomes in acinar cells, as assessed by lysosomal pH and LysoTracker DND-26 fluorescence intensity. In addition, TNF-\u03b1 treatment induced transcription factor EB (TFEB) redistribution in SMG-C6 cells, which was consistent with the changes observed in IgG4-RS patients. TNF-\u03b1 increased the phosphorylation of extracellular signal\u2013regulated kinase (ERK) 1\/2, and inhibition of ERK1\/2 by U0126 reversed TNF-\u03b1\u2013induced TFEB redistribution, lysosomal dysfunction, and autophagic flux suppression. These findings suggest that TNF-\u03b1 is a key cytokine related to acinar cell injury in IgG4-RS through ERK1\/2-mediated autophagic flux suppression.<\/jats:p>","DOI":"10.1177\/0022034519871890","type":"journal-article","created":{"date-parts":[[2019,8,28]],"date-time":"2019-08-28T19:07:41Z","timestamp":1567019261000},"page":"1386-1396","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["TNF-\u03b1 Suppresses Autophagic Flux in Acinar Cells in IgG4-Related Sialadenitis"],"prefix":"10.1177","volume":"98","author":[{"given":"X.","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University, the Hong Kong University of Science and Technology Medical Center, Shenzhen, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.N.","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.Y.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.T.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University, the Hong Kong University of Science and Technology Medical Center, Shenzhen, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University, the Hong Kong University of Science and Technology Medical Center, Shenzhen, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.Y.","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University, the Hong Kong University of Science and Technology Medical Center, Shenzhen, P.R. China"},{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.L.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.Y.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University, the Hong Kong University of Science and Technology Medical Center, Shenzhen, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,8,28]]},"reference":[{"key":"bibr1-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.08.013"},{"key":"bibr2-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2015.03.003"},{"key":"bibr3-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.08.128"},{"key":"bibr4-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0945-7"},{"key":"bibr5-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1186\/1748-717X-7-64"},{"key":"bibr6-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1998.275.4.C1151"},{"key":"bibr7-0022034519871890","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00228"},{"key":"bibr8-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200103083441005"},{"key":"bibr9-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1507-6"},{"key":"bibr10-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-018-9318-8"},{"key":"bibr11-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.169"},{"issue":"6","key":"bibr12-0022034519871890","first-page":"970","volume":"29","author":"Kang EH","year":"2011","journal-title":"Clin Exp Rheumatol"},{"key":"bibr13-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1097\/IOP.0000000000000625"},{"key":"bibr14-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1356977"},{"key":"bibr15-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1100356"},{"key":"bibr16-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2018.1537962"},{"key":"bibr17-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1038\/446745a"},{"key":"bibr18-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.12.018"},{"key":"bibr19-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2018.02.005"},{"key":"bibr20-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0698-y"},{"key":"bibr21-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209139"},{"key":"bibr22-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.12.1330"},{"key":"bibr23-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8007"},{"key":"bibr24-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2015.07.002"},{"key":"bibr25-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1038\/srep05206"},{"key":"bibr26-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1177\/0022034515590796"},{"key":"bibr27-0022034519871890","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.54.2581"},{"key":"bibr28-0022034519871890","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201798804"},{"key":"bibr29-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1007\/s11626-997-0137-8"},{"key":"bibr30-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.07.112"},{"key":"bibr31-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1104650"},{"key":"bibr32-0022034519871890","doi-asserted-by":"publisher","DOI":"10.3109\/s10165-011-0571-z"},{"key":"bibr33-0022034519871890","doi-asserted-by":"publisher","DOI":"10.3181\/0806-RM-209"},{"key":"bibr34-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1002\/med.21394"},{"key":"bibr35-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.05.008"},{"key":"bibr36-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12169"},{"key":"bibr37-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2011.06.002"},{"key":"bibr38-0022034519871890","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439496"},{"key":"bibr39-0022034519871890","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2018.1536364"},{"key":"bibr40-0022034519871890","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18010157"}],"container-title":["Journal of Dental Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0022034519871890","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0022034519871890","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0022034519871890","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:08:16Z","timestamp":1777496896000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0022034519871890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,28]]},"references-count":40,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,11]]}},"alternative-id":["10.1177\/0022034519871890"],"URL":"https:\/\/doi.org\/10.1177\/0022034519871890","relation":{},"ISSN":["0022-0345","1544-0591"],"issn-type":[{"value":"0022-0345","type":"print"},{"value":"1544-0591","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,28]]}}}