The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts

J Clin Invest. 1998 May 15;101(10):2080-91. doi: 10.1172/JCI1359.


The bradykinin B1-receptor is strongly upregulated under chronic inflammatory conditions. However, the mechanism and reason are not known. Because a better understanding of the mechanism of the upregulation will help in understanding its potential importance in inflammation, we have studied the molecular mechanism of B1-receptor upregulation in cultured human lung fibroblasts (IMR 90) in response to IL-1beta and the B1-agonist [des-Arg10]-kallidin. We show that treatment of human IMR 90 cells by IL-1beta stimulates the expression of both B1-receptor mRNA and protein. The latter was studied by Western blot analysis using antipeptide antibodies directed against the COOH-terminal part of the human B1-receptor. We furthermore report the novel observation that the B1-receptor is upregulated by its own agonist which was completely blocked by the specific B1-antagonist [des-Arg10-Leu9]-kallidin, indicating an upregulation entirely mediated through cell surface B1-receptors. The increased population of B1-receptors was functionally coupled as exemplified by an enhancement of the B1-agonist induced increase in free cytosolic calcium. Upregulation by the B1-agonist was blocked by a specific protein kinase C inhibitor. B1-agonist-induced upregulation was correlated to the induction of transcription factor nuclear factor kappaB (NF-kappaB) which efficiently bound to the NF-kappaB-like sequence located in the promoter region of the human B1-receptor gene. This correlation was further confirmed by reporter gene assays which showed that this NF-kappaB-like sequence, in the B1-receptor promoter context, could contribute to IL-1beta and DLBK-induced B1-receptor transcription activation, and by the effect of NF-kappaB inhibitor pyrrolidinedithiocarbamate which diminished both B1-receptor upregulation and NF-kappaB activation. NF-kappaB is now recognized as a key inflammatory mediator which is activated by the B1-agonist but which is also involved in B1-receptor upregulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Cholera Toxin / pharmacology
  • DNA-Binding Proteins / metabolism
  • Fibroblasts
  • Humans
  • Inflammation / physiopathology
  • Interleukin-1 / pharmacology
  • Kallidin / agonists
  • Kallidin / analogs & derivatives*
  • Kallidin / pharmacology
  • Lung / drug effects*
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • Pyrrolidines / pharmacology
  • RNA, Messenger / metabolism
  • Receptor, Bradykinin B1
  • Receptors, Bradykinin / metabolism*
  • Thiocarbamates / pharmacology
  • Transcriptional Activation / drug effects*
  • Up-Regulation / drug effects*
  • Virulence Factors, Bordetella / pharmacology


  • DNA-Binding Proteins
  • Interleukin-1
  • NF-kappa B
  • Pyrrolidines
  • RNA, Messenger
  • Receptor, Bradykinin B1
  • Receptors, Bradykinin
  • Thiocarbamates
  • Virulence Factors, Bordetella
  • bradykinin, Lys-Leu(8)-desArg(9)-
  • prolinedithiocarbamate
  • pyrrolidine dithiocarbamic acid
  • Kallidin
  • kallidin, des-Arg(10)-
  • Cholera Toxin
  • Proline