Activation of protein formation and cell division by bradykinin and des-Arg9-bradykinin.

Abstract

We employed des-Argo-bradykinin to investigate the relation between bradykinin-induced prostaglandin (PG) synthesis and bradykinin-induced protein accumulation.In this feedback control system, bradykinininduced PG synthesis limits bradykinin-induced protein production.At low concentration (5 X 10-'M), des-Args-bradykinin was significantly less active than bradykinin in stimulating the formation of prostaglandins by human fetal lung fibroblasts in culture.At high concentration (5 X M), bradykinin induced a 24% increase in protein formation, while des-Arg*-bradykinin induced a 61% increase in collagen formation and an 80% increase in total protein accumulation.In the presence of indomethacin, bradykinin-induced protein formation was increased further, whereas des-Arg"-bradykinin-induced protein formation was unchanged.The bradykinin derivative increased the production of types I and 111 procollagens without affecting the distribution of procollagen types.The incorporation of ['Hlthymidine into DNA in lung fibroblast cultures was increased 3-fold by des-Arg"-bradykinin alone or by bradykinin in combination with indomethacin.Des-Arg"-[Leu*]bradykinin inhibited the des- Ar8-bradykinin-induced protein formation and cell division. These data indicate that both bradykinin and des-Args-bradykinin stimulate protein formation and cell division; des-Arge-bradykinin alone stimulates protein formation and cell division without activating PG synthesis and PG feedback control.Bradykinin is generated during inflammatory reactions by the action of plasma kallikrein.The hormone stimulates prostaglandin synthesis by many cell types including fibroblasts and endothelial cells (1-3).These PGs' mediate many but not all of the bradykinin-induced cellular responses.We determined previously that bradykinin-induced PG synthesis in fibroblast cultures was maximally stimulated when the bradykinin concentration was 5 X lo-' M or greater (2).Bradykinin at 5 X lo-' M also induced a slight increase in protein accumulation.This bradykinin-induced protein accumulation was increased further when bradykinin was used