{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:45:34Z","timestamp":1788320734824,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T00:00:00Z","timestamp":1603670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["19K10078"],"award-info":[{"award-number":["19K10078"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Aspiration pneumonia is a major health problem owing to its high mortality rate in elderly people. The secretion of proinflammatory cytokines such as interleukin (IL)-8 and IL-6 by respiratory epithelial cells, which is induced by infection of respiratory bacteria such as Streptococcus pneumoniae, contributes to the onset of pneumonia. These cytokines thus play a key role in orchestrating inflammatory responses in the lower respiratory tract. In contrast, chronic periodontitis, a chronic inflammatory disease caused by the infection of periodontopathic bacteria, typically Porphyromonas gingivalis, is one of the most prevalent microbial diseases affecting humans globally. Although emerging evidence has revealed an association between aspiration pneumonia and chronic periodontitis, a causal relationship between periodontopathic bacteria and the onset of aspiration pneumonia has not been established. Most periodontopathic bacteria are anaerobic and are therefore unlikely to survive in the lower respiratory organs of humans. Therefore, in this study, we examined whether simple contact by heat-inactivated P. gingivalis induced proinflammatory cytokine production by several human respiratory epithelial cell lines. We found that P. gingivalis induced strong IL-8 and IL-6 secretion by BEAS-2B bronchial epithelial cells. P. gingivalis also induced strong IL-8 secretion by Detroit 562 pharyngeal epithelial cells but not by A549 alveolar epithelial cells. Additionally, Toll-like receptor (TLR) 2 but not TLR4 was involved in the P. gingivalis-induced proinflammatory cytokine production. Furthermore, P. gingivalis induced considerably higher IL-8 and IL-6 production than heat-inactivated S. pneumoniae. Our results suggest that P. gingivalis is a powerful inflammatory stimulant for human bronchial and pharyngeal epithelial cells and can stimulate TLR2-mediated cytokine production, thereby potentially contributing to the onset of aspiration pneumonia.<\/jats:p>","DOI":"10.3390\/jcm9113433","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T10:38:35Z","timestamp":1603708715000},"page":"3433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Exposure to Porphyromonas gingivalis Induces Production of Proinflammatory Cytokine via TLR2 from Human Respiratory Epithelial Cells"],"prefix":"10.3390","volume":"9","author":[{"given":"Norihisa","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Periodontology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"},{"name":"Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Yokoe","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"},{"name":"Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-844X","authenticated-orcid":false,"given":"Yorimasa","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-4267","authenticated-orcid":false,"given":"Kenichi","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/ggi.13839","article-title":"Association between sarcopenia and pneumonia in older people","volume":"20","author":"Okazaki","year":"2019","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/00001432-200306000-00002","article-title":"Host innate defenses in the lung: The role of cytokines","volume":"16","author":"Strieter","year":"2003","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/ppul.20735","article-title":"Airway epithelial cell signaling in response to bacterial pathogens","volume":"43","author":"Gomez","year":"2007","journal-title":"Pediatr. Pulmonol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1164\/ajrccm.153.1.8542140","article-title":"Compartmentalized IL-8 and elastase release within the human lung in unilateral pneumonia","volume":"153","author":"Boutten","year":"1996","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1183\/09031936.96.09091858","article-title":"Bronchoalveolar and systemic cytokine profiles in patients with ARDS, severe pneumonia and cardiogenic pulmonary oedema","volume":"9","author":"Lohmeyer","year":"1996","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4553","DOI":"10.1128\/iai.61.11.4553-4559.1993","article-title":"High levels of interleukin-8 in the blood and alveolar spaces of patients with pneumonia and adult respiratory distress syndrome","volume":"61","author":"Montravers","year":"1993","journal-title":"Infect. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1034\/j.1399-3003.1999.14a37.x","article-title":"Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: A pilot study","volume":"14","author":"Ewig","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","article-title":"Periodontal diseases","volume":"366","author":"Pihlstrom","year":"2005","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1574-6968.2012.02579.x","article-title":"Porphyromonas gingivalis: An invasive and evasive opportunistic oral pathogen","volume":"333","author":"Bostanci","year":"2012","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.2174\/138161207783018554","article-title":"Porphyromonas gingivalis Mediated Periodontal Disease and Atherosclerosis: Disparate Diseases with Commonalities in Pathogenesis Through TLRs","volume":"13","author":"Iii","year":"2007","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.4049\/jimmunol.0802906","article-title":"Reactivation of Latent HIV-1 Infection by the Periodontopathic BacteriumPorphyromonas gingivalisInvolves Histone Modification","volume":"182","author":"Imai","year":"2009","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.biochi.2011.12.001","article-title":"The periodontal pathogen Porphyromonas gingivalis induces the Epstein\u2013Barr virus lytic switch transactivator ZEBRA by histone modification","volume":"94","author":"Imai","year":"2012","journal-title":"Biochimie"},{"key":"ref_13","first-page":"3","article-title":"Oral health care and aspiration pneumonia in frail older people: A systematic literature review","volume":"30","author":"Vanobbergen","year":"2012","journal-title":"Gerodontology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1046\/j.1532-5415.2001.49113.x","article-title":"Aspiration Pneumonia: Dental and Oral Risk Factors in an Older Veteran Population","volume":"49","author":"Terpenning","year":"2001","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jiac.2016.09.013","article-title":"Quantitative detection of periodontopathic bacteria in lower respiratory tract specimens by real-time PCR","volume":"23","author":"Nagaoka","year":"2017","journal-title":"J. Infect. Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.resinv.2018.08.003","article-title":"The microbiome in the lower respiratory tract","volume":"56","author":"Yatera","year":"2018","journal-title":"Respir. Investig."},{"key":"ref_17","first-page":"56","article-title":"Anaerobic infections of the lung and pleural space","volume":"110","author":"Bartlett","year":"1974","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.anaerobe.2011.12.004","article-title":"Anaerobic bacterial infection of the lung","volume":"18","author":"Bartlett","year":"2012","journal-title":"Anaerobe"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1177\/154405910808700418","article-title":"Oral Health and Mortality Risk from Pneumonia in the Elderly","volume":"87","author":"Awano","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1902\/annals.2003.8.1.54","article-title":"Associations Between Periodontal Disease and Risk for Nosocomial Bacterial Pneumonia and Chronic Obstructive Pulmonary Disease. A Systematic Review","volume":"8","author":"Scannapieco","year":"2003","journal-title":"Ann. Periodontol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.ejim.2013.12.001","article-title":"The management of community-acquired pneumonia in the elderly","volume":"25","author":"Faverio","year":"2014","journal-title":"Eur. J. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1111\/febs.12768","article-title":"Role of the histone H3 lysine 9 methyltransferase Suv39 h1 in maintaining Epsteinn-Barr virus latency in B95-8 cells","volume":"281","author":"Imai","year":"2014","journal-title":"FEBS J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5314","DOI":"10.1128\/IAI.00681-10","article-title":"Human Airway Epithelial Cell Responses to Neisseria lactamica and Purified Porin via Toll-Like Receptor 2-Dependent Signaling","volume":"78","author":"Liu","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e600","DOI":"10.1111\/j.1365-2567.2008.03041.x","article-title":"Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas","volume":"128","author":"Rydberg","year":"2009","journal-title":"Immunology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.micinf.2010.10.003","article-title":"Pneumolysin-induced CXCL8 production by nasopharyngeal epithelial cells is dependent on calcium flux and MAPK activation via Toll-like receptor 4","volume":"13","author":"Dogan","year":"2011","journal-title":"Microbes Infect."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-KappaB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0002-9343(00)00507-6","article-title":"Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis","volume":"109","author":"Hill","year":"2000","journal-title":"Am. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1159\/000237218","article-title":"Interleukin-8 in airway inflammation in patients with asthma and chronic obstructive pulmonary disease","volume":"109","author":"Nocker","year":"1996","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1902\/jop.2007.060078","article-title":"Comparison of Subgingival Bacterial Sampling with Oral Lavage for Detection and Quantification of Periodontal Pathogens by Real-Time Polymerase Chain Reaction","volume":"78","author":"Boutaga","year":"2007","journal-title":"J. Periodontol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1177\/00220345950740111201","article-title":"Salivary Levels of Suspected Periodontal Pathogens in Relation to Periodontal Status and Treatment","volume":"74","author":"Torkko","year":"1995","journal-title":"J. Dent. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1378\/chest.124.1.328","article-title":"Aspiration Pneumonia and Dysphagia in the Elderly","volume":"124","author":"Marik","year":"2003","journal-title":"Chest"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00408-011-9334-z","article-title":"Effect of Aging on Cough and Swallowing Reflexes: Implications for Preventing Aspiration Pneumonia","volume":"190","author":"Ebihara","year":"2011","journal-title":"Lung"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.cyto.2008.11.005","article-title":"Porphyromonas gingivalis culture supernatants differentially regulate interleukin-1beta and interleukin-18 in human monocytic cells","volume":"45","author":"Hamedi","year":"2009","journal-title":"Cytokine"},{"key":"ref_34","first-page":"512","article-title":"Interleukin-1 receptor-associated kinase-M in gingival epithelial cells attenuates the inflammatory response elicited byPorphyromonas gingivalis","volume":"45","author":"Takahashi","year":"2010","journal-title":"J. Periodontal Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1902\/jop.2010.100004","article-title":"Gram-Negative Periodontal Bacteria Induce the Activation of Toll-Like Receptors 2 and 4, and Cytokine Production in Human Periodontal Ligament Cells","volume":"81","author":"Sun","year":"2010","journal-title":"J. Periodontol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1111\/j.1600-0765.2006.00890.x","article-title":"Differences in innate immune responses upon stimulation with gram-positive and gram-negative bacteria","volume":"41","author":"Tietze","year":"2006","journal-title":"J. Periodontal Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3109\/00016357.2013.834535","article-title":"Different effects of P. gingivalis LPS and E. coli LPS on the expression of interleukin-6 in human gingival fibroblasts","volume":"72","author":"Andrukhov","year":"2014","journal-title":"Acta Odontol. Scand."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8296","DOI":"10.4049\/jimmunol.177.12.8296","article-title":"Cutting Edge: TLR2 Is Required for the Innate Response toPorphyromonas gingivalis: Activation Leads to Bacterial Persistence and TLR2 Deficiency Attenuates Induced Alveolar Bone Resorption","volume":"177","author":"Burns","year":"2006","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1159\/000314686","article-title":"Pathogen-mediated inflammatory atherosclerosis is mediated in part via Toll-like receptor 2-induced inflammatory responses","volume":"2","author":"Hayashi","year":"2010","journal-title":"J. Innate Immun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1111\/j.1462-5822.2006.00730.x","article-title":"Differential interactions of fimbriae and lipopolysaccharide from Porphyromonas gingivalis with the Toll-like receptor 2-centred pattern recognition apparatus","volume":"8","author":"Hajishengallis","year":"2006","journal-title":"Cell Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1128\/IAI.01036-12","article-title":"A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis","volume":"81","author":"Jain","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1128\/IAI.06180-11","article-title":"Free Lipid A Isolated from Porphyromonas gingivalis Lipopolysaccharide Is Contaminated with Phosphorylated Dihydroceramide Lipids: Recovery in Diseased Dental Samples","volume":"80","author":"Nichols","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat. Immunol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/11\/3433\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:28:13Z","timestamp":1760178493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/11\/3433"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,26]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["jcm9113433"],"URL":"https:\/\/doi.org\/10.3390\/jcm9113433","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,26]]}}}