title: 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.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U388, Institut Louis BUGNARD, CHU Rangueil, 31052 Toulouse, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Schanstra
authors.forename: E
authors.initials: E
authors.lastname: Bataillé
authors.forename: M E
authors.initials: ME
authors.lastname: Marin Castaño
authors.forename: Y
authors.initials: Y
authors.lastname: Barascud
authors.forename: C
authors.initials: C
authors.lastname: Hirtz
authors.forename: J B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: C
authors.initials: C
authors.lastname: Pecher
authors.forename: F
authors.initials: F
authors.lastname: Gauthier
authors.forename: J P
authors.initials: JP
authors.lastname: Girolami
authors.forename: J L
authors.initials: JL
authors.lastname: Bascands
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007375:Interleukin-1 / Q000494:pharmacology; D007609:Kallidin / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D013859:Thiocarbamates; D010566:Virulence Factors, Bordetella; C082229:bradykinin, Lys-Leu(8)-desArg(9)-; C066229:prolinedithiocarbamate; C020972:pyrrolidine dithiocarbamic acid; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D002772:Cholera Toxin; D011392:Proline