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


CONCLUSIONS
Repression of NF-kappaB and AP-1 activities by H1-receptor antagonists involves H1-receptor-dependent and -independent mechanisms but not 5-LO.
Roumestan
C
C
Inserm, U454, Montpellier, France.
Henriquet
C
C
Gougat
C
C
Michel
A
A
Bichon
F
F
Portet
K
K
Jaffuel
D
D
Mathieu
M
M
D000704:Analysis of Variance; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005821:Genetic Techniques; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018946:Chemokine CCL5; D006634:Histamine H1 Antagonists; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D011969:Receptors, Histamine H1; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D001094:Arachidonate 5-Lipoxygenase; D013755:Tetradecanoylphorbol Acetate