Abstract
Bradykinin B1 receptors (B1R) are rapidly induced after tissue trauma and are thought to be involved in maintaining the inflammatory response. Little is known about the intracellular signaling pathways mediating B1R induction in response to stress and inflammation. Here, we show that up-regulation of B1R by B1R agonist and interleukin-1β (IL-1β) occur through distinct but synergistic pathways in IMR-90 human lung fibroblasts. Incubation of cells with the B1R agonist desArg10kallidin (desArg10KD; 100 nM) and IL-1β (500 pg/ml) resulted in a 3- and 4-fold increase, respectively, in B1R by 6 h, whereas coincubation of these factors produced up to a 20-fold increase. Furthermore, coincubation increased the potency of IL-1β by 2-fold. Both the individual and the synergistic responses were sensitive to genistein, a general tyrosine kinase inhibitor. On the other hand, only the desArg10KD response and the synergistic response were sensitive to the p38 mitogen-activated protein kinase inhibitor SB 203580. Furthermore, only the synergistic response was sensitive to the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate. Despite B1R up-regulation in A549 human lung epithelial cells by desArg10KD or IL-1β individually, these factors did not act synergistically in this cell line. In conclusion, our results reinforce the view that kinins act in concert with proinflammatory cytokines to enhance selectively the inflammatory response of certain lung cells to kinins through distinct but synergistic intracellular signaling mechanisms. Thus, kinins may exert a pivotal role in maintaining and modulating feed-forward inflammatory processes in the lung.
Footnotes
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This work was supported by a grant from the Cystic Fibrosis Foundation (to S.B.P.), a Fellowship from the Childrens Hospital of Los Angeles Research Institute (to S.B.P.), and National Institutes of Health Grants NHLBI HL60231 (D.W.) and GM41659 (to L.M.F.L.L.). This work was presented in part at the American Thoracic Society, Canada, May 2000. Am J Respir Crit Care Med161:A166.
- Abbreviations:
- BK
- bradykinin
- KD
- kallidin
- GPCR
- G protein-coupled receptor
- IL-1β
- interleukin-1β
- NF-κB
- nuclear factor-κB
- MAPK
- mitogen-activated protein kinase
- DMEM
- Dulbecco's modified Eagle's medium
- PBS
- phosphate-buffered saline
- RT-PCR
- reverse transcription-polymerase chain reaction
- PTK
- protein tyrosine kinase
- MAP
- mitogen-activated protein
- ERK
- extracellular signal-regulated kinase
- PDTC
- pyrrolidine dithiocarbamate
- Received December 18, 2000.
- Accepted March 6, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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