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


METHODS
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.


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
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.
Holden
N S
NS
Department of Cell Biology and Anatomy, Respiratory Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Gong
W
W
King
E M
EM
Kaur
M
M
Giembycz
M A
MA
Newton
R
R
D000256:Adenoviridae / Q000235:genetics; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006632:Histamine / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D011968:Receptors, Histamine / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D006633:Histamine Antagonists; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011968:Receptors, Histamine; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D006632:Histamine