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

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 kappa B (NF-kappa B)-dependent transcription and cytokine release. Experimental approach: Using BEAS-2B bronchial epithelial cells, NF-kappa B-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 TNF alpha-stimulated BEAS-2B cells maximally potentiated NF-kappa B-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-kappa B-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 TNF alpha-induced NF-kappa B-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, H3 and H4 receptor agonists did not affect TNF alpha-induced NF-kappa B-dependent transcription, or IL-6 and IL-8 release at concentrations below 10 mM. The anti-inflammatory glucocorticoid, dexamethasone, inhibited the histamine enhanced NF-kappa B-dependent transcription and IL-6 and IL-8 release. Conclusions and implications: Potentiation of NF-kappa B-dependent transcription and inflammatory cytokine release by histamine predominantly involves receptors of the H1 receptor subtype. These data support an anti-inflammatory role for H1 receptor antagonists by preventing the transcription and release of pro-inflammatory cytokines.