Research article summary (published 30 May 2008):

Histamine H1-receptor antagonists inhibit nuclear factor-kappaB and activator protein-1 activities via H1-receptor-dependent and -independent mechanisms.

Full Abstract

BACKGROUND: Histamine H1-receptor antagonists are used to relieve the symptoms of an immediate allergic reaction. They have additional anti-inflammatory effects that could result from an inhibition of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). The implication of the H1-receptor in these effects is controversial. Diphenhydramine is a first-generation H1-receptor antagonist while mizolastine and desloratadine are second-generation compounds. Mizolastine is also an inhibitor of 5-lipoxygenase (5-LO), an enzyme that has been involved in NF-kappaB activation. OBJECTIVE: We measured the ability of antihistamines to reverse histamine-induced smooth muscle contraction, an effect that involves the H1-receptor. We then investigated whether these drugs affect NF-kappaB and AP-1 activities in A549 lung epithelial cells, and whether this potential regulation involves H1-receptor and 5-LO. METHODS: Muscle tone was measured on tracheal segments of guinea-pigs. The H1-receptor was overexpressed by transfection and detected by Western blotting and immunofluorescence microscopy. NF-kappaB and AP-1 activities were assessed by reporter gene assays in cells overexpressing or not overexpressing the H1-receptor. Production of regulated upon activation, normal T cell expressed andsecreted (RANTES), a chemokine whose expression is induced through NF-kappaB, was measured using an immunoassay. RESULTS: H1-receptor antagonists reversed histamine-induced contraction in a dose-dependent manner. Induction of AP-1 and NF-kappaB activities by histamine and the down-regulatory effect of antihistamines required overexpression of the H1-receptor. In contrast, when tumour necrosis factor-alpha and a phorbol ester were used to stimulate NF-kappaB and AP-1 activities, respectively, repression of these activities did not involve the H1-receptor. Indeed, repression was triggered only by a subset of H1-receptor antagonists and was not stronger after overexpression of the H1-receptor. Mizolastine and desloratadine dose-dependently decreased tumour necrosis factor-alpha-induced production of RANTES. Diphenhydramine, H2- and H3-receptor antagonists as well as selective inhibitors of 5-LO were ineffective in this assay. CONCLUSION: Repression of NF-kappaB and AP-1 activities by H1-receptor antagonists involves H1-receptor-dependent and -independent mechanisms but not 5-LO.

Author information

Author/s: Roumestan, C (C); Henriquet, C (C); Gougat, C (C); Michel, A (A); Bichon, F (F); Portet, K (K); Jaffuel, D (D); Mathieu, M (M);

Affiliation: Inserm, U454, Montpellier, France.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy), published in England. (Language: eng)

Reference: 2008-Jun; vol 38 (issue 6) : pp 947-56

Dates: Created 2008/05/23; Completed 2008/07/28;

PMID: 18498541, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Analysis of Variance Animals Arachidonate 5-Lipoxygenase - antagonists & inhibitors; metabolism Cell Line Chemokine CCL5 - metabolism Epithelial Cells - drug effects; metabolism Genetic Techniques Guinea Pigs Histamine - pharmacology Histamine H1 Antagonists - pharmacology Humans Lipoxygenase Inhibitors - pharmacology

Lipoxygenase Inhibitors - pharmacology Lung - cytology; drug effects; metabolism Male Muscle, Smooth - drug effects NF-kappa B - metabolism Plasmids - genetics Receptors, Histamine H1 - genetics; metabolism T-Lymphocytes - drug effects; metabolism Tetradecanoylphorbol Acetate - pharmacology Trachea - drug effects Transcription Factor AP-1 - metabolism Tumor Necrosis Factor-alpha - pharmacology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Chemokine CCL5 (0) ; Histamine H1 Antagonists (0) ; Lipoxygenase Inhibitors (0) ; NF-kappa B (0) ; Receptors, Histamine H1 (0) ; Transcription Factor AP-1 (0) ; Tumor Necrosis Factor-alpha (0) ; Tetradecanoylphorbol Acetate (16561-29-8) ; Histamine (51-45-6) ; Arachidonate 5-Lipoxygenase (EC 1.13.11.34)

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