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

Br J Pharmacol. 2007 Nov;152(6):891-902. doi: 10.1038/sj.bjp.0707457. Epub 2007 Sep 24.

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 kappaB (NF-kappaB)-dependent transcription and cytokine release.

Experimental approach: Using BEAS-2B bronchial epithelial cells, NF-kappaB-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 TNFalpha-stimulated BEAS-2B cells maximally potentiated NF-kappaB-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-kappaB-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 TNFalpha-induced NF-kappaB-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 TNFalpha-induced NF-kappaB-dependent transcription, or IL-6 and IL-8 release at concentrations below 10 microM. The anti-inflammatory glucocorticoid, dexamethasone, inhibited the histamine enhanced NF-kappaB-dependent transcription and IL-6 and IL-8 release.

Conclusions and implications: Potentiation of NF-kappaB-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Anti-Inflammatory Agents / pharmacology
  • Blotting, Western
  • Bronchi / cytology
  • Cell Line
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Gene Expression / drug effects
  • Genetic Vectors
  • Histamine / pharmacology*
  • Histamine Antagonists / pharmacology
  • Humans
  • I-kappa B Proteins / biosynthesis
  • I-kappa B Proteins / genetics
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / physiology*
  • Receptors, Histamine / biosynthesis
  • Receptors, Histamine / drug effects
  • Receptors, Histamine / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Histamine Antagonists
  • I-kappa B Proteins
  • Inflammation Mediators
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • Receptors, Histamine
  • Tumor Necrosis Factor-alpha
  • Dexamethasone
  • Histamine