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

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.