M. Takano et al., MURINE FIBROBLASTS SYNTHESIZE AND SECRETE KININOGEN IN RESPONSE TO CYCLIC-AMP, PROSTAGLANDIN E(2) AND TUMOR-NECROSIS-FACTOR, Biochimica et biophysica acta. Molecular cell research, 1265(2-3), 1995, pp. 189-195
Fibroblasts prepared from the meninges of newborn mice or from mouse e
mbryos, as well as fibroblast L929 cells, secreted an immunoreactive m
aterial (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 l
ow-molecular-weight kininogen antibody, showed that ir-kininogen had a
molecular weight of 80000 and that it contained a kinin moiety. N-ter
minal amino acid sequence of the ir-kininogen was consistent with that
of mouse L-kininogen. The ir-kininogen produced by fibroblasts releas
ed a kinin by incubating with trypsin and mouse submandibular gland ka
llikrein, and it was identified as bradykinin by means of high-perform
ance liquid chromatography, indicating that mouse fibroblasts produce
and secrete a kininogen. Forskolin, prostaglandin E(2) and tumor necro
sis factor cu stimulated the production of ir-kininogen by meningeal f
ibroblasts, 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, prosta
glandin E2 and tumor necrosis factor. Therefore locally produced kinin
ogen is implicated in pathogenesis of inflammation.