Bradykinin synergistically stimulates interleukin 6 production in human gingival fibroblasts challenged with interleukin 1 or tumour necrosis factor alpha.
The production of interleukin 6 (IL-6) was studied in human gingival fibroblasts challenged with bradykinin (BK), in the presence or absence of either tumour necrosis factor alpha (TNF-alpha) or interleukin 1 (IL-1). The inflammatory mediator BK as well as the cytokines TNF-alpha and IL-beta dose dependently stimulated IL-6 production in gingival fibroblasts. When the cells were treated simultaneously with BK and either IL-1 beta or TNF-alpha, the inflammatory mediator BK synergistically upregulated IL-6 production in a dose-dependent manner. The BK B1 receptor agonist des-arg9-BK as well as the BK B2 receptor agonist Lys-BK also induced IL-6 production and synergistically enhanced the effect of IL-1 and TNF-alpha on the production of IL-6. The upregulation of IL-6 production induced by BK was abolished by the anti-inflammatory agent dexamethasone (DEX) and the phospholipase A2 (PLA2) inhibitor 4-bromphenacyl bromide (BPB). Treatment of the cells with the cyclooxygenase (COX) inhibitor flurbiprofen resulted in a minor reduction of the stimulatory effect of BK. The results show that BK together with IL-1 or TNF-alpha act in concert to enhance IL-6 production and that the synergy was obtained by both the BK B1 and the BK B2 receptor agonist. The study indicates that the synergy between BK and IL-1 or TNF-alpha on IL-6 production is mediated partly at the level of PLA2 and partly at the level of COX. The synergism between the pro-inflammatory mediator BK and the cytokines IL-1 or TNF-alpha indicates that gingival fibroblasts, by producing cytokines, affect the local immune response in the connective tissue and thereby play a role in the pathogenesis of periodontal disease.
Modéer
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Department of Pediatric Dentistry, Faculty of Odontology, Karolinska Institute, Huddinge, Sweden.
Andurén
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Yucel-Lindberg
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D000098:Acetophenones / Q000494:pharmacology; D000293:Adolescent; D001920:Bradykinin / Q000494:pharmacology*; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D018002:Receptors, Bradykinin / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000098:Acetophenones; D007375:Interleukin-1; D015850:Interleukin-6; D018002:Receptors, Bradykinin; D014409:Tumor Necrosis Factor-alpha; D005480:Flurbiprofen; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate; C006821:4-bromophenacyl bromide; D001920:Bradykinin