Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-kappa B

Bradykinin, a mediator of inflammation, is produced in the brain during tra uma and stroke. It is thought to open the blood-brain barrier, although the mechanism is unclear. We have investigated, therefore, the effect of brady kinin on the expression of interleukin-6 (IL-6), a putative modulator of th e blood-brain barrier, in astrocytes. IL-6 gene transcription was evaluated by transient transfection of the human IL-6 promoter linked to the lucifer ase gene. In murine astrocytes, bradykinin stimulated IL-6 secretion and ge ne transcription, The effect of bradykinin was blocked by KN-93, an inhibit or of Ca2+/calmodulin-dependent protein kinases, and by bisindolylmaleimide I, an inhibitor of protein kinase C, suggesting the involvement of these p rotein kinases. Mutations in the multiple response element and the binding site for nuclear factor-kappa B (NF-kappa B), but not in other known elemen ts of the IL-6 promoter, interfered with induction of IL-6 transcription. T he involvement of NF-kappa B was supported further by the finding that over expression of nmI kappa B alpha, a stable inhibitor of NF-kappa B, inhibite d the induction of IL-6 by bradykinin. Bradykinin activated NF-kappa B in p rimary astrocytes as shown by increased DNA binding of NF-kappa B. These da ta demonstrate that bradykinin stimulates IL-6 expression through activatio n of NF-kappa B, which may explain several inflammatory effects of bradykin in.