BRADYKININ INHIBITION OF EGF-INDUCED AND PDGF-INDUCED DNA-SYNTHESIS IN HUMAN FIBROBLASTS

Bradykinin exhibits proliferative influences in several types of cells ; however, in the present study, bradykinin did not promote DNA synthe sis but actually inhibited the DNA synthesis induced by epidermal grow th factor (EGF) and platelet-derived growth factor (PDGF) in human gin gival fibroblasts (HGF). This dose-dependent inhibitory effect was a s pecific intracellular interaction in that increasing concentrations of EGF did not counteract the inhibitory actions of bradykinin when adde d at 100 nM. The phosphoinositide-calcium signaling cascade is a likel y point of interaction for the inhibitory influences of bradykinin; ho wever, no interactions between bradykinin and EGF were observed with t he generation of inositol phosphates or intracellular calcium fluxes. The inhibitory influences of bradykinin do not appear to be the result of a transmodulation of the EGF receptor, since EGF-mediated autophos phorylation was not negatively affected by bradykinin. Bradykinin-stim ulated prostaglandin E2 (PGE2) release was potentiated by EGF, and, in the presence of indomethacin, the inhibition of the EGF-induced DNA s ynthesis by bradykinin was minimized. The results presented demonstrat e that bradykinin can inhibit EGF- and PDGF-induced DNA synthesis and suggest that PGE2 synthesis is responsible for the observed bradykinin inhibition of EGF-induced DNA synthesis.