{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:01:18Z","timestamp":1789624878201,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T00:00:00Z","timestamp":1741996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP21K06383"],"award-info":[{"award-number":["JP21K06383"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer\u2019s disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1\u03b2 (IL-1\u03b2) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30\u20131000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1\u03b2 up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 \u03bcg\/mL) and OMVs (150 \u03bcg of protein\/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the \u03b22 adrenergic receptor (A\u03b22R)-mediated pathway. NF-\u03baB, which is activated by the Pg LPS\/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1\u03b2 production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-\u03baB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-\u03baB p65 to the I\u03baB site, resulting in the synergistic augmentation of the IL-1\u03b2 promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9\/p52\/RelB-mediated pathway. The A\u03b22R\/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1\u03b2 in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1\u03b2 in response to Pg LPS and OMVs through distinct mechanisms.<\/jats:p>","DOI":"10.3390\/ijms26062660","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T06:36:23Z","timestamp":1742193383000},"page":"2660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1\u03b2 Production in BV-2 Microglia Through Differential Mechanisms"],"prefix":"10.3390","volume":"26","author":[{"given":"Sakura","family":"Muramoto","sequence":"first","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumika","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honoka","family":"Ikeda","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misato","family":"Jo","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uzuki","family":"Takemori","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiharu","family":"Morimoto","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0423-2143","authenticated-orcid":false,"given":"Hidetoshi","family":"Tozaki-Saitoh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy at Fukuoka, International University of Health and Welfare, Okawa 831-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Inoue","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2610-3203","authenticated-orcid":false,"given":"Hiroshi","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Yasuda Women\u2019s University, Hiroshima 731-0153, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/1040841X.2022.2163613","article-title":"Porphyromonas gingivalis and the pathogenesis of Alzheimer's disease","volume":"50","author":"Liu","year":"2024","journal-title":"Crit. 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