Murine fibroblasts synthesize and secrete kininogen in response to cyclic-AMP, prostaglandin E2 and tumor necrosis factor.

Fibroblasts prepared from the meninges of newborn mice or from mouse embryos, as well as fibroblast L929 cells, secreted an immunoreactive material (ir-kininogen) against rabbit anti-mouse low-molecular-weight kininogen antibody in response to dibutyryl cAMP. Western blots using a bradykinin-directed monoclonal, as well as a polyclonal anti-mouse low-molecular-weight kininogen antibody, showed that ir-kininogen had a molecular weight of 80,000 and that it contained a kinin moiety. N-terminal amino acid sequence of the ir-kininogen was consistent with that of mouse L-kininogen. The ir-kininogen produced by fibroblasts released a kinin by incubating with trypsin and mouse submandibular gland kallikrein, and it was identified as bradykinin by means of high-performance liquid chromatography, indicating that mouse fibroblasts produce and secrete a kininogen. Forskolin, prostaglandin E2 and tumor necrosis factor alpha stimulated the production of ir-kininogen by meningeal fibroblasts, whereas neither dibutyryl cAMP nor these agents influenced kininogen production by mouse hepatocytes in primary cultures. These results demonstrated that fibroblasts are a source of kininogen in the mouse, and that it is regulated by the inflammatory mediators, prostaglandin E2 and tumor necrosis factor. Therefore locally produced kininogen is implicated in pathogenesis of inflammation.