BRADYKININ SYNERGISTICALLY STIMULATES INTERLEUKIN-6 PRODUCTION IN HUMAN GINGIVAL FIBROBLASTS CHALLENGED WITH INTERLEUKIN-1 OR TUMOR-NECROSIS-FACTOR-ALPHA

The production of interleukin 6 (IL-6) was studied in human gingival f ibroblasts 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-1 beta dose dependently stimulated IL-6 production in gingival fibroblasts. When the cells were treated simultaneously with BK and e ither TL-1 beta or TNF-alpha, the inflammatory mediator BK synergistic ally upregulated IL-6 production in a dose-dependent manner, The BK B1 receptor agonist des-arg(9)-BK as well as the BK B2 receptor agonist Lys-BK also induced IL-6 production and synergistically enhanced the e ffect of IL-1 and TNF-alpha on the production of IL-6, The upregulatio n of IL-6 production induced by BK was abolished by the anti-inflammat ory agent dexamethasone (DEX) and the phospholipase A(2) (PLA(2)) inhi bitor 4-bromphenacyl bromide (BPB), Treatment of the cells with the cy clooxygenase (COX) inhibitor flurbiprofen resulted in a minor reductio n of the stimulatory effect of BK, The results show that BK together w ith IL-1 or TNF-alpha act in concert to enhance IL-6 production and th at the synergy,vas obtained by both the BK B1 and the BK B2 receptor a gonist, The study indicates that the synergy between BK and IL-1 or TN F-alpha on IL-6 production is mediated partly at the level of PLA(2) a nd partly at the level of COX, The synergism between the pro-inflammat ory mediator BK and the cytokines IL-1 or TNF-alpha indicates that gin gival fibroblasts, by producing cytokines, affect the local immune res ponse in the connective tissue and thereby play a role in the pathogen esis of periodontal disease. (C) 1997 Academic Press Limited.