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Research ArticleArticle

Post-Transcriptional Regulation of Bradykinin B1 and B2 Receptor Gene Expression in Human Lung Fibroblasts by Tumor Necrosis Factor-α: Modulation by Dexamethasone

El-Bdaoui Haddad, Alison J. Fox, Jonathan Rousell, Gillian Burgess, Peter McIntyre, Peter J. Barnes and K. Fan Chung
Molecular Pharmacology June 2000, 57 (6) 1123-1131;
El-Bdaoui Haddad
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Alison J. Fox
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Jonathan Rousell
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Gillian Burgess
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Peter McIntyre
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Peter J. Barnes
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K. Fan Chung
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Abstract

The cellular and molecular mechanisms governing bradykinin B1 and B2 receptor expression and function are poorly understood. We investigated the regulation of both B1 and B2 receptors in human embryonic lung fibroblasts (HEL 299) by the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). TNF-α and IL-1β both induced a rapid and transient increase in B1 and B2 receptor mRNA expression that was maximal by 2 h, accompanied by an increase in B1 and B2 receptor protein, as measured by radioligand binding assay with [3H]des-Arg10-kallidin, and [3H]bradykinin, respectively. The induced B1 receptors were functionally coupled, because the B1 agonist, des-Arg10-kallidin, induced an increase in arachidonic acid release in TNF-α-stimulated cells but not in control cells. The induction of B1 and the up-regulation of B2 receptors by TNF-α was partly mediated through activation of p38 mitogen-activated protein kinase and that of B2 receptor by protein kinase A. TNF-α and IL-1β regulation of both B1 and B2 receptors was inhibited by dexamethasone. When compared with vehicle-treated cells, dexamethasone increased the rate of decline of both B1 and B2 receptor mRNAs. Nuclear run-on experiments demonstrate that the induction of B1 and the up-regulation of B2 receptors as well as the inhibitory effect of dexamethasone are entirely mediated through post-transcriptional mechanisms.

Footnotes

  • Send reprint requests to: Dr. El-Bdaoui Haddad, Department of Pharmacology, Aventis Pharmaceuticals, Rainham Road South Dagenham, Essex RM10 7XS, United Kingdom. E-mail: el-bdaoui.haddad{at}aventis.com

  • This work was supported by a Wellcome Trust Career Development Award (to A.J.F.) and by a fellowship from the European Union (to E.-B.H.).

  • Abbreviations:
    BK
    bradykinin
    KD
    kallidin
    TNF-α
    tumor necrosis factor α
    IL-1β
    interleukin 1β
    MAPK
    mitogen-activated protein kinase
    ERK
    extracellular signal-regulated kinase
    JNK
    c-Jun NH2-terminal protein kinase
    PKA
    cAMP-dependent protein kinase
    PKC
    protein kinase C
    SSC
    sodium chloride/sodium citrate buffer
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    PAGE
    polyacrylamide gel electrophoresis
    TES
    2-{[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino}ethanesulfonic acid
    HBSS
    Hanks' balanced salt solution
    [3H]AA
    [3H]arachidonic acid
    • Received October 12, 1999.
    • Accepted February 8, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (6)
Molecular Pharmacology
Vol. 57, Issue 6
1 Jun 2000
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Research ArticleArticle

Post-Transcriptional Regulation of Bradykinin B1 and B2 Receptor Gene Expression in Human Lung Fibroblasts by Tumor Necrosis Factor-α: Modulation by Dexamethasone

El-Bdaoui Haddad, Alison J. Fox, Jonathan Rousell, Gillian Burgess, Peter McIntyre, Peter J. Barnes and K. Fan Chung
Molecular Pharmacology June 1, 2000, 57 (6) 1123-1131;

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Research ArticleArticle

Post-Transcriptional Regulation of Bradykinin B1 and B2 Receptor Gene Expression in Human Lung Fibroblasts by Tumor Necrosis Factor-α: Modulation by Dexamethasone

El-Bdaoui Haddad, Alison J. Fox, Jonathan Rousell, Gillian Burgess, Peter McIntyre, Peter J. Barnes and K. Fan Chung
Molecular Pharmacology June 1, 2000, 57 (6) 1123-1131;
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