Abstract
Bradykinin (BK) B1 receptors are thought to exert a pivotal role in maintaining and modulating inflammatory processes. They are not normally present under physiological situations but are induced under physiopathological conditions. In isolated human umbilical vein (HUV), a spontaneous BK B1 receptor up-regulation and sensitization process has been demonstrated. Based on pyrrolidine-dithiocarbamate inhibition, it has been proposed that this phenomenon is dependent on nuclear factor-κB (NF-κB) activation. The aim of this study was to further evaluate the NF-κB pathway involvement on BK B1 receptor sensitization in isolated HUV, using several pharmacological tools. In 5-h incubated rings, either the I-κB kinase inhibitor 3-(4-methylphenylsulfonyl)-2-propenenitrile (Bay 11–7082) or the proteasome activity inhibitor Z-Leu-Leu-Leu-CHO (MG-132) inhibited the development of the BK B1 receptor-sensitized contractile responses. Furthermore, pro-inflammatory cytokine interleukin-6 (IL-6) produced a leftward shift of the concentration-response curve to the BK B1 receptor agonist, whereas anti-inflammatory cytokines interleukin-4 (IL-4) and tumor growth factor-β1 (TGF-β1) produced a rightward shift of the responses to des-Arg9-BK in our preparations. Taken together, these results point to NF-κB as a key intermediary in the activation of the expression of BK B1 receptor-sensitized responses in HUV and support the role of inflammatory mediators in the modulation of this process.
Footnotes
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↵1 Current address: Department of Neuroscience, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston. MA. 02115.
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↵2 Current address: Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077-Goettingen, Germany.
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This research was supported by grants from the Universidad de Buenos Aires (UBA Grant TM-049) and by the Fundación A. J. Roemmers.
- Abbreviations:
- BK
- bradykinin
- 5-HT
- 5-hydroxytryptamine or serotonin
- HUV
- human umbilical vein
- IL
- interleukin
- NF-κB
- nuclear factor-κB
- PDTC
- pyrrolidine-dithiocarbamate
- Bay 11–7082
- 3-(4-methylphenylsulfonyl)-2-propenenitrile
- MG-132
- Z-Leu-Leu-Leu-CHO
- TGF-β1
- tumor growth factor-β1
- TNF-α
- tumor necrosis factor-α
- Received September 17, 2001.
- Accepted March 4, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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