Elevated salivary activity of mast cell chymase of periodontitis patients, and a new bradykinin generation cascade, mediating the cross-talks between mast cell and gingival fibroblast

Int Immunopharmacol. 2021 Dec;101(Pt A):108269. doi: 10.1016/j.intimp.2021.108269. Epub 2021 Oct 21.


Activated-mast cells (MCs) within gingival-tissue of chronic-periodontitis (CP) patients, release various inflammatory-factors. Bradykinin is a nine-amino-acid peptide and pro-inflammatory mediator, produced through factor-XII-cascade or tryptase-cascade. The ability of MC-chymase in bradykinin generation has not been discussed yet. This study investigated the salivary levels of MC-chymase, high molecular weight kininogen (HMWK) and bradykinin of CP patients; examined the potential of MC-proteases in bradykinin production using biochemistry-models; and explored the effects of bradykinin on gingival fibroblasts (GFs). Saliva-samples were collected; MC-protease activities were detected; HMWK cleavage was assessed by western-blot and SDS-PAGE; bradykinin levels were measured using immunoassay. Primary GFs were extracted and cultured with or without bradykinin; cell-viability, gelatine-zymography and flow-cytometry were applied. Immunocytochemistry and western-blot were used to detect intracellular protein expressions of bradykinin-stimulated GFs. The data showed that the salivary-levels of MC-proteases, bradykinin, HMWK, and lactoferrin of CP-patients were increased. HMWK was cleaved by MC-chymase in-vitro, resulting in bradykinin generation. Bradykinin promoted cell proliferation, cell cycle and matrix-metalloproteinase-2(MMP-2) activity, and increased intracellular expressions of nuclear-factor-kappa-B(NF-κB), focal-adhesion-kinase(FAK), transforming-growth-factor-β(TGF-β), P38, P53 of GFs. MC-chymase promotes bradykinin production to stimulate GFs and to continue inflammation during CP development. A new BK-generation cascade found in this study provides a new basis for the pathogenesis of CP and the mechanism of continuous inflammation. The activation of MC-chymase/bradykinin-generation cascade depends on HMWK level and MC-chymase activity under inflammatory condition. MC-chymase contributes to bradykinin production, mediating the cross-talks between MCs and GFs. MC-chymase can be used as a therapeutic target and a salivary biomarker in this case.

Keywords: Bradykinin; Chronic periodontitis; Gingival fibroblast; HMWK; Mast cell chymase; Saliva.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Bradykinin / biosynthesis*
  • Case-Control Studies
  • Cell Communication / immunology
  • Cell Cycle / immunology
  • Cell Proliferation
  • Chronic Periodontitis / immunology*
  • Chronic Periodontitis / pathology
  • Chymases / analysis
  • Chymases / metabolism*
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Gingiva / cytology
  • Gingiva / immunology
  • Gingiva / pathology
  • Healthy Volunteers
  • Humans
  • Kininogen, High-Molecular-Weight / analysis
  • Lactoferrin / analysis
  • Male
  • Mast Cells / enzymology
  • Mast Cells / immunology
  • Middle Aged
  • Saliva / chemistry*
  • Saliva / immunology


  • Kininogen, High-Molecular-Weight
  • LTF protein, human
  • Lactoferrin
  • CMA1 protein, human
  • Chymases
  • Bradykinin