The Functional Interaction of EGF and PDGF With Bradykinin in the Proliferation of Human Gingival Fibroblasts

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Abstract
Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-BB are both involved in periodontal wound healing. Each of these growth factors exerts a positive proliferative effect on cells of the periodontium in vitro. However, in vivo the peptide bradykinin is one of a complex array of mediators present in addition to these growth factors. The purposes of this investigation were to: 1) evaluate bradykinin interactions with EGF and PDGF-BB altering cell proliferation in cultured human gingival fibroblasts (HGF), periodontal ligament cells (HPDL), and cells derived from alveolar bone (HOB); and 2) determine at the signal transduction level the mechanism of interaction between EGF and bradykinin in HGF. EGF and PDGF-BB stimulated DNA synthesis in a concentration-dependent manner, as measured by [3H] thymidine incorporation. Bradykinin alone did not alter significantly basal DNA synthesis values; however, bradykinin in combination with EGF reduced DNA synthesis to nearly basal levels and bradykinin in combination with PDGF reduced the DNA synthesis over 50%. Examination of the interactions between bradykinin and EGF signal transduction pathways revealed that PGE2, release was increased in the presence of bradykinin and EGF (167 ± 33% to 317 ± 29%). The bradykinin-stimulated PGE2 release was completely abolished by indomethacin. Indomethacin also was found to block the bradykinin inhibition of EGF-induced DNA synthesis. Additional evidence supporting a mechanism involving PGE2, in the bradykinin inhibition of growth factor-stimulated DNA synthesis was that EGF-induced DNA synthesis was inhibited by exogenously added PGE2 but not by endothelin, Vasopressin, or des-Arg9 bradykinin. Forskolin and dibutyryl cAMP also were found to inhibit EGF-induced DNA synthesis, suggesting that cAMP was involved in the mechanism of inhibition. In conclusion, the present study demonstrates that both EGF- and PDGF-BB-induced proliferative responses are inhibited by bradykinin in cells of the periodontium. The signaling mechanism of the bradykinin inhibition of EGF appears to be mediated by PGE2 through a cAMPdependent pathway in HGFs. J Periodontol 1995;66:429–437.

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