Potentiation of NF-κB-dependent transcription and inflammatory mediator release by histamine in human airway epithelial cells

N. S. Holden, W. Gong, E. M. King, M. Kaur, M. A. Giembycz, R. Newton

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background and purpose: In asthma, histamine contributes to bronchoconstriction, vasodilatation and oedema, and is associated with the late phase response. The current study investigates possible inflammatory effects of histamine acting on nuclear factor κB (NF-κB)-dependent transcription and cytokine release. Experimental approach: Using BEAS-2B bronchial epithelial cells, NF-κB-dependent transcription and both release and mRNA expression of IL-6 and IL-8 were examined by reporter assay, ELISA and quantitative RT-PCR. Histamine receptors were detected using qualitative RT-PCR and function examined using selective agonists and antagonists. Key results: Addition of histamine to TNFα-stimulated BEAS-2B cells maximally potentiated NF-κB-dependent transcription 1.8 fold, whereas IL-6 and IL-8 protein release were enhanced 7.3- and 2.7-fold respectively. These responses were, in part, NF-κB-dependent and were associated with 2.6- and 1.7-fold enhancements of IL-6 and IL-8 mRNA expression. The H 1 receptor antagonist, mepyramine, caused a rightward shift in the concentration-response curves of TNFα-induced NF-κB-dependent transcription (pA 2=9.91) and release of IL-6 (pA 2=8.78) and IL-8 (pA 2=8.99). Antagonists of histamine H 2, H 3 and H 4 receptors were without effect. Similarly, H 3 and H 4 receptor agonists did not affect TNFα-induced NF-κB-dependent transcription, or IL-6 and IL-8 release at concentrations below 10 μM. The anti-inflammatory glucocorticoid, dexamethasone, inhibited the histamine enhanced NF-κB-dependent transcription and IL-6 and IL-8 release. Conclusions and implications: Potentiation of NF-κB-dependent transcription and inflammatory cytokine release by histamine predominantly involves receptors of the H 1 receptor subtype. These data support an anti-inflammatory role for H 1 receptor antagonists by preventing the transcription and release of pro-inflammatory cytokines. © 2007 Nature Publishing Group All rights reserved.
    Original languageEnglish
    Pages (from-to)891-902
    Number of pages11
    JournalBritish Journal of Pharmacology
    Volume152
    Issue number6
    DOIs
    Publication statusPublished - Nov 2007

    Keywords

    • BEAS-2B epithelial cells
    • Glucocorticoid
    • Histamine
    • IL-6
    • IL-8
    • Inflammation
    • Mepyramine
    • NF-κB

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