{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:05:22Z","timestamp":1790172322486,"version":"4.1.0"},"reference-count":58,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Periodontitis is an inflammatory disease of polymicrobial origin affecting the tissues supporting the tooth. The oral anaerobic bacterium<jats:named-content content-type=\"genus-species\">Porphyromonas gingivalis<\/jats:named-content>, which is implicated as an important pathogen for chronic periodontitis, triggers a series of host inflammatory responses that promote the destruction of periodontal tissues. Among the virulence factors of<jats:named-content content-type=\"genus-species\">P. gingivalis<\/jats:named-content>, hemoglobin receptor protein (HbR) is a major protein found in culture supernatants. In this study, we investigated the roles of HbR in the production of inflammatory mediators. We found that HbR induced interleukin-8 (IL-8) production in the human gingival epithelial cell line Ca9-22. p38 mitogen-activated protein kinase (MAPK) and extracellular signal-related kinase 1\/2 (Erk1\/2) were activated in HbR-stimulated Ca9-22 cells. Inhibitors of p38 MAPK (SB203580) and Erk1\/2 (PD98059) blocked HbR-induced IL-8 production. Additionally, HbR stimulated the translocation of NF-\u03baB-p65 to the nucleus, consistent with enhancement of IL-8 expression by activation of the NF-\u03baB pathway. In addition, small interfering RNA (siRNA) targeting activating transcription factor 2 (ATF-2) or cyclic AMP-response element-binding protein (CREB) inhibited HbR-induced IL-8 production. Moreover, pretreatment with SB203580 and PD98059 reduced HbR-induced phosphorylation of CREB and ATF-2, respectively. Combined pretreatment with an inhibitor of NF-\u03baB (BAY11-7082) and SB203580 was more efficient in inhibiting the ability of HbR to induce IL-8 production than pretreatment with either BAY11-7082 or SB203580 alone. Thus, in Ca9-22 cells, the direct activation of p38 MAPK and Erk1\/2 by HbR caused the activation of the transcription factors ATF-2, CREB, and NF-\u03baB, thus resulting in the induction of IL-8 production.<\/jats:p>","DOI":"10.1128\/iai.01140-12","type":"journal-article","created":{"date-parts":[[2013,10,15]],"date-time":"2013-10-15T00:16:11Z","timestamp":1381796171000},"page":"202-211","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Hemoglobin Receptor Protein from Porphyromonas gingivalis Induces Interleukin-8 Production in Human Gingival Epithelial Cells through Stimulation of the Mitogen-Activated Protein Kinase and NF-\u03baB Signal Transduction Pathways"],"prefix":"10.1128","volume":"82","author":[{"given":"Yuki","family":"Fujita","sequence":"first","affiliation":[{"name":"Department of Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 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