Bradykinin Induces Interleukin-6 Expression in Astrocytes Through Activation of Nuclear Factor-κB

Authors

  • Markus Schwaninger,

  • Svea Sallmann,

  • Nicole Petersen,

  • Armin Schneider,

  • Simone Prinz,

  • Towia A. Libermann,

  • Matthias Spranger


  • Abbreviations used : DMEM, Dulbecco's modified Eagle medium ; IL-6, interleukin-6 ; MRE, multiple response element ; NF-κB, nuclear factor-κB ; PKC, protein kinase C ; TPA, phorbol 12-myristate 13-acetate.

Address correspondence and reprint requests to Dr. M. Schwaninger at Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

Abstract

Abstract : Bradykinin, a mediator of inflammation, is produced in the brain during trauma and stroke. It is thought to open the blood-brain barrier, although the mechanism is unclear. We have investigated, therefore, the effect of bradykinin on the expression of interleukin-6 (IL-6), a putative modulator of the blood-brain barrier, in astrocytes. IL-6 gene transcription was evaluated by transient transfection of the human IL-6 promoter linked to the luciferase gene. In murine astrocytes, bradykinin stimulated IL-6 secretion and gene transcription. The effect of bradykinin was blocked by KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinases, and by bisindolyl-maleimide I, an inhibitor of protein kinase C, suggesting the involvement of these protein kinases. Mutations in the multiple response element and the binding site for nuclear factor-κB (NF-κB), but not in other known elements of the IL-6 promoter, interfered with induction of IL-6 transcription. The involvement of NF-κB was supported further by the binding that overexpression of nmIκBα, a stable inhibitor of NF-κB, inhibited the induction of IL-6 by bradykinin. Bradykinin activated NF-κB in primary astrocytes as shown by increased DNA binding of NF-κB. These data demonstrate that bradykinin stimulates IL-6 expression through activation of NF-κB, which may explain several inflammatory effects of bradykinin.

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