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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

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Item Type:Article
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
Creators Name:Schanstra, J.P. and Bataille, E. and Castano, M.E.M. and Barascud, Y. and Hirtz, C. and Pesquero, J.B. and Pecher, C. and Gauthier, F. and Girolami, J.P. and Bascands, J.L.
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.
Keywords:Amino Acid Sequence, Bordetella Virulence Factors, Bradykinin B1 Receptor, Bradykinin Receptors, Cell Line, Cholera Toxin, DNA-Binding Proteins, Fibroblasts, Inflammation, Interleukin-1, Kallidin, Lung, Messenger RNA, Molecular Sequence Data, NF-kappa B, Proline, Pyrrolidines, Thiocarbamates, Transcriptional Activation, Up-Regulation
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:2080-2091
Date:15 May 1998
Official Publication:https://doi.org/10.1172/JCI1359
PubMed:View item in PubMed

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