title: Fusobacterium nucleatum and human beta-defensins modulate the release of antimicrobial chemokine CCL20/macrophage inflammatory protein 3α.
abstract: Cells of the innate immune system regulate immune responses through the production of antimicrobial peptides, chemokines, and cytokines, including human beta-defensins (hBDs) and CCL20. In this study, we examined the kinetics of primary human oral epithelial cell (HOEC) production of CCL20 and hBDs in response to Fusobacterium nucleatum, a commensal bacterium of the oral cavity, which we previously showed promotes HOEC induction of hBDs. HOECs secrete maximal levels of CCL20 at 6 h, following stimulation by F. nucleatum cell wall (FnCW). The kinetics of CCL20 release is distinct from that of hBD-2 and -3, which peaks after 24 h and 48 h of FnCW stimulation, respectively. FnCW-induced release of CCL20 by HOECs requires both transcriptional and translational activation. Release of CCL20 by HOECs is inhibited by brefeldin A, suggesting that it is secreted through a vesicle transport pathway. Other epithelium-derived agents that FnCW induces, such as hBD-2, hBD-3, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), are also able to release CCL20. By focusing on mitogen-activated protein kinases, we show that both extracellular signal-regulated kinase 1/2 and p38, but not JNK, are required for hBD-, TNF-α-, and IL-1β-induced secretion of CCL20 by HOECs. The ability of FnCW and its induced hBDs to produce proinflammatory cytokines and CCL20 suggests the broad role of F. nucleatum and human antimicrobial peptides in primary immune responses elicited by oral epithelium.
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4905, USA.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Ghosh
authors.forename: Sanhita
authors.initials: S
authors.lastname: Gupta
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism*; D016967:Fusobacterium nucleatum / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023083:beta-Defensins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D023181:Antimicrobial Cationic Peptides; C108355:CCL20 protein, human; D054418:Chemokine CCL20; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D020929:Mitogen-Activated Protein Kinase Kinases