Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1beta and tumor necrosis factor alpha.
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-1beta and TNFalpha on the production of IL-8. The stimulatory effect of BK on the IL-1beta- or TNFalpha-stimulated IL-8 production was reduced in the presence of BK B2 receptor antagonist HOE 140, whereas the B1 receptor antagonist Lys-(des-arg9, Leu8)-BK had no effect. Similar to BK, the calcium ionophore A23187 also upregulated the stimulatory effect of IL-1beta and TNFalpha on IL-8 production. The protein kinase C (PKC) inhibitor bisindolylmaleimide, BIS, significantly reduced the stimulatory effect of BK on IL-1beta and TNFalpha 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-1beta as well as the IL-1beta-stimulated IL-8 production. In conclusion, this study shows that BK upregulates IL-1beta- and TNFalpha-stimulated IL-8 production via BK B2 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.
Brunius
Gustaf
G
Department of Pediatric Dentistry, Institute of Odontology, Karolinska Institutet, Huddinge, Sweden.
Domeij
Helena
H
Gustavsson
Agneta
A
Yucel-Lindberg
Tülay
T
D000293:Adolescent; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D065094:Bradykinin B2 Receptor Antagonists; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D007476:Ionophores / Q000494:pharmacology; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D043782:Receptor, Bradykinin B2; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D065094:Bradykinin B2 Receptor Antagonists; D007093:Imidazoles; D007211:Indoles; D007375:Interleukin-1; D016209:Interleukin-8; D007476:Ionophores; D008301:Maleimides; D011725:Pyridines; D043782:Receptor, Bradykinin B2; D014409:Tumor Necrosis Factor-alpha; C082229:bradykinin, Lys-Leu(8)-desArg(9)-; D007609:Kallidin; D000001:Calcimycin; C065679:icatibant; D011493:Protein Kinase C; D048370:MAP Kinase Kinase 2; C088060:bisindolylmaleimide; C093642:SB 203580; D001920:Bradykinin