title: Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1beta and tumor necrosis factor alpha.
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-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.
authors.affiliation: Department of Pediatric Dentistry, Institute of Odontology, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Brunius
authors.forename: Helena
authors.initials: H
authors.lastname: Domeij
authors.forename: Agneta
authors.initials: A
authors.lastname: Gustavsson
authors.forename: Tülay
authors.initials: T
authors.lastname: Yucel-Lindberg
mesh_terms: 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
chemical_list: 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