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-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 language | English (US) |
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Pages (from-to) | 2080-2091 |
Number of pages | 12 |
Journal | Journal of Clinical Investigation |
Volume | 101 |
Issue number | 10 |
DOIs | |
State | Published - May 15 1998 |
Externally published | Yes |
Keywords
- B-receptor
- Bradykinin
- Gene expression
- Inflammation
- NF-κB
ASJC Scopus subject areas
- Medicine(all)