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

Joost P. Schanstra, Emmanuelle Bataillé, Maria E. Marin Castaño, Yannick Barascud, Christophe Hirtz, João B. Pesquero, Christiane Pecher, Francis Gauthier, Jean Pierre Girolami, Jean Loup Bascands

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167 Scopus citations


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-1β and the B1-agonist [des-Arg10]- kallidin. We show that treatment of human IMR 90 cells by IL-1β 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 κB (NF- κB) which efficiently bound to the NF-κB-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-κB-like sequence, in the B1-receptor promoter context, could contribute to IL-1β and DLBK-induced B1-receptor transcription activation, and by the effect of NF-κB inhibitor pyrrolidinedithiocarbamate which diminished both B1- receptor upregulation and NF-κB activation. NF-κB is now recognized as a key inflammatory mediator which is activated by the B1-agonist but which is also involved in B1-receptor upregulation.

Original languageEnglish (US)
Pages (from-to)2080-2091
Number of pages12
JournalJournal of Clinical Investigation
Issue number10
StatePublished - May 15 1998
Externally publishedYes


  • B-receptor
  • Bradykinin
  • Gene expression
  • Inflammation
  • NF-κB

ASJC Scopus subject areas

  • Medicine(all)


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