Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1β and tumor necrosis factor α

Abstract

The proinflammatory mediator bradykinin (BK) is suggested to play an important role in the pathogenesis of various inflammatory diseases including periodontitis. In this study, BK per se stimulated interleukin-8 (IL-8) production in human gingival fibroblasts in vitro. Furthermore, BK upregulated the stimulatory effect of the cytokines IL-1β and TNFα on the production of IL-8. The stimulatory effect of BK on the IL-1β- or TNFα-stimulated IL-8 production was reduced in the presence of BK B 2 receptor antagonist HOE 140, whereas the B 1 receptor antagonist Lys-(des-arg 9, Leu 8)-BK had no effect. Similar to BK, the calcium ionophore A23187 also upregulated the stimulatory effect of IL-1β and TNFα on IL-8 production. The protein kinase C (PKC) inhibitor bisindolylmaleimide, BIS, significantly reduced the stimulatory effect of BK on IL-1β and TNFα increased IL-8 production but did not affect the production of IL-8 stimulated by cytokines alone. The specific p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 reduced IL-8 production stimulated by the combination of BK and IL-1β as well as the IL-1β-stimulated IL-8 production. In conclusion, this study shows that BK upregulates IL-1β- and TNFα-stimulated IL-8 production via BK B 2 receptor and that PKC signal pathway seems to be involved in the upregulation of the cytokine-induced IL-8 production in gingival fibroblasts. This stimulatory effect of BK on IL-8 production may contribute to the maintenance of the gingival inflammation and enhanced risk for destruction of gingival connective tissue.