title: Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin.
abstract: Actinobacillus actinomycetemcomitans is implicated in the pathogenesis of localized aggressive periodontitis, and has the capacity to express a cytolethal distending toxin (Cdt). Gingival fibroblasts (GF) are resident cells of the periodontium, which can express several osteolytic cytokines. The aims of this study were a) to investigate the role of Cdt in A. actinomycetemcomitans-induced expression of osteolytic cytokines and their cognate receptors in GF and b) to determine if the previously demonstrated induction of receptor activator of NFkappaB ligand (RANKL) by A. actinomycetemcomitans is mediated by these pro-inflammatory cytokines or by prostaglandin E(2) (PGE(2)). A. actinomycetemcomitans clearly induced interleukin (IL)-6, IL-1beta, and to a minimal extent, tumor necrosis factor (TNF)-alpha mRNA expression. At the protein level, IL-6 but not IL-1beta or TNF-alpha expression was stimulated. The mRNA expression of the different receptor subtypes recognizing IL-6, IL-1beta and TNF-alpha was not affected. A cdt-knockout strain of A. actinomycetemcomitans had similar effects on cytokine and cytokine receptor mRNA expression, compared to its parental wild-type strain. Purified Cdt stimulated IL-6, but not IL-1beta or TNF-alpha protein biosynthesis. Antibodies neutralizing IL-6, IL-1 or TNF-alpha, and the PGE(2) synthesis inhibitor indomethacin, did not affect A. actinomycetemcomitans-induced RANKL expression. In conclusion, a) A. actinomycetemcomitans induces IL-6 production in GF by a mechanism largely independent of its Cdt and b) A. actinomycetemcomitans-induced RANKL expression in GF occurs independently of IL-1, IL-6, TNF-alpha, or PGE(2).
authors.affiliation: Division of Oral Microbiology, Department of Odontology, S-901 87 Umeå University, Umeå, Sweden. george.belibasakis@odont.umu.se
authors.forename: G N
authors.initials: GN
authors.lastname: Belibasakis
authors.forename: A
authors.initials: A
authors.lastname: Johansson
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Lagergård
authors.forename: S
authors.initials: S
authors.lastname: Kalfas
authors.forename: U H
authors.initials: UH
authors.lastname: Lerner
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000235:genetics / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D005881:Gingiva / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017472:Receptors, Interleukin-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053574:Receptors, Interleukin-1 Type II; D019947:Receptors, Interleukin-6 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000494:pharmacology
chemical_list: D001427:Bacterial Toxins; D002352:Carrier Proteins; D016207:Cytokines; C507763:IL1RN protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D019947:Receptors, Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012795:Sialoglycoproteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C067044:cytolethal distending toxin; D015232:Dinoprostone; D007213:Indomethacin