{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:31:04Z","timestamp":1792798264823,"version":"4.5.0"},"reference-count":64,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2019\/35\/B\/NZ5\/01823"],"award-info":[{"award-number":["2019\/35\/B\/NZ5\/01823"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,5,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              The interaction between pathogenic microorganisms and stromal cells, in particular fibroblasts, significantly contributes to the pathogenesis of many bacterially driven diseases. In periodontitis, oral pathogens penetrate the epithelial barrier and aggravate ongoing gingival inflammation by promoting the production of inflammatory mediators, such as prostaglandin E2 (PGE2). This study aimed to investigate the functional consequences of the interplay between oral pathogens and a pro-inflammatory environment in the activation of the PGE2 pathway in primary human gingival fibroblasts (GFs). GF infection with\n              <jats:italic toggle=\"yes\">Fusobacterium nucleatum<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">Porphyromonas gingivalis,<\/jats:italic>\n              or\n              <jats:italic toggle=\"yes\">Filifactor alocis<\/jats:italic>\n              in the presence of tumor necrosis factor (TNF) led to synergistic induction of cyclooxygenase-2 (COX-2), a key enzyme in the PGE2 synthesis pathway, as well as secretion of PGE2. A similar synergy in COX-2 upregulation was observed upon GF infection with oral pathogens in the presence of IL-1\u03b1, IL-1\u03b2, and interferon-\u03b1 (IFN-\u03b1). This effect required toll-like receptor-2 (TLR2) and the p38 MAP kinase activation and was specific for fibroblasts as infection of macrophages or keratinocytes with oral pathogens in the proinflammatory environment did not cause synergistic COX-2 induction. Finally, we demonstrated that conditioned media from GFs infected with\n              <jats:italic toggle=\"yes\">F. nucleatum<\/jats:italic>\n              under inflammatory conditions amplified the expression of the neutrophil chemokine\n              <jats:italic toggle=\"yes\">IL8<\/jats:italic>\n              in macrophages and confirmed that this effect was mediated by synergistic induction of PGE2 in GFs. Collectively, we identify a new mechanism of stromal-immune cross-talk that is driven by synergistic PGE2 induction by oral pathogens and inflammatory cytokines in GFs and may contribute to excessive macrophage activation and neutrophil infiltration in periodontitis.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Periodontitis is a highly prevalent, dysbiosis-driven chronic inflammatory disease that not only leads to tooth loss but also is associated with severe systemic diseases. In this work, we describe a novel mechanism responsible for excessive production of PGE2, which is a potent inflammatory mediator that significantly contributes to the pathogenesis of periodontitis. We found that infection of GFs with many species of oral pathogens in the presence of inflammatory cytokines produced by the host leads to synergistic induction of COX-2 expression and PGE2 production. We found that this fibroblast-specific amplification of the COX-2-PGE2 axis by oral pathogens and cytokines is driven by the p38 MAP kinase and promotes enhanced expression of a key neutrophil chemokine by macrophages. These studies have thus enabled the identification of a new mechanism of host-pathogen interactions in periodontitis, improving our understanding of the roles of GFs and their cross-talk with immune cells in disease pathogenesis.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00046-25","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T10:35:43Z","timestamp":1743762943000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Synergistic induction of PGE2 by oral pathogens and TNF promotes gingival fibroblast-driven stromal-immune cross-talk in periodontitis"],"prefix":"10.1128","volume":"16","author":[{"given":"Elwira","family":"Nieboga","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University","place":["Krak\u00f3w, Poland"]},{"name":"Doctoral 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Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Kwitniewski","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University","place":["Krak\u00f3w, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Migaczewski","sequence":"additional","affiliation":[{"name":"2nd Department of General Surgery, Jagiellonian University Medical College","place":["Krak\u00f3w, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Czesnikiewicz-Guzik","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Preventive Dentistry and Oral Medicine, Faculty of Medicine, Jagiellonian University Medical College","place":["Krak\u00f3w, Poland"]},{"name":"Oral Sciences, University of Glasgow Dental School, School of Medicine, Dentistry & Nursing, College of Medical, Veterinary and Life 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