Abstract
The regulation of the kallikrein-kinin system is an important mechanism controlling vasodilation and promoting inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) in regulating kinin B1 and B2 receptor expression in human gingival fibroblasts and in mouse gingiva. Both P. gingivalis LPS and the synthetic TLR2 agonist Pam2CSK4 increased kinin receptor transcripts. Silencing of TLR2, but not of TLR4, inhibited the induction of kinin receptor transcripts by both P. gingivalis LPS and Pam2CSK4. Human gingival fibroblasts (HGF) exposed to Pam2CSK4 increased binding sites for bradykinin (BK, B2 receptor agonist) and des-Arg10-Lys-bradykinin (DALBK, B1 receptor agonist). Pre-treatment of HGF for 24 h with Pam2CSK4 resulted in increased PGE2 release in response to BK and DALBK. The increase of B1 and B2 receptor transcripts by P. gingivalis LPS was not blocked by IL-1β neutralizing antibody; TNF-α blocking antibody did not affect B1 receptor up-regulation, but partially blocked increase of B2 receptor mRNA. Injection of P. gingivalis LPS in mouse gingiva induced an increase of B1 and B2 receptor mRNA. These data show that activation of TLR2 in human gingival fibroblasts as well as in mouse gingival tissue leads to increase of B1 and B2 receptor mRNA and protein.
Highlights
Expression of IL6 mRNA has previously been reported to be upregulated by P. gingivalis LPS27; in the present experiments, increased IL6 mRNA was seen at the same concentrations as those stimulating kinin receptor expression
We report that the mRNAs encoding for the B1 and B2 kinin receptors are among those genes regulated by LPS from the periodontopathogenic bacterium P. gingivalis, both in vitro in human gingival fibroblasts and in vivo in mouse gingiva
It has been demonstrated that expression of Toll-like receptor 2 (TLR2) mRNA and protein, one of the receptors activated by P. gingivalis is enhanced by activation of B2 kinin receptor, indicating a bidirectional regulation of kinin receptors and TLR2 by their cognate ligands[30]
Summary
Kinins are generated by the release from kininogens through the enzymatic action of kallikreins Since their discovery, these peptides are well known as pro-inflammatory molecules by increasing vasodilation, vascular permeability and cellular migration[1]. We reported that P. gingivalis stimulates osteoclast formation in vitro and causes inflammation induced bone loss in vivo through activation of TLR215. This observation and the fact that periodontitis induced by P. gingivalis can not be observed in mice with genetic deletion of TLR2 indicates that TLR2 is important for the pathogenic properties of P. gingivalis in periodontal disease[16,17,18]
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