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

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 factorkappa B (NF-kB). 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-kB 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-kB 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-kB 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-kB, was measured using an immunoassay. Results H1-receptor antagonists reversed histamine-induced contraction in a dose-dependent manner. Induction of AP-1 and NF-kB activities by histamine and the down-regulatory effect of antihistamines required overexpression of the H1-receptor. In contrast, when tumour necrosis factor-a and a phorbol ester were used to stimulate NF-kB 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-a-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-kB and AP-1 activities by H1-receptor antagonists involves H1-receptor-dependent and -independent mechanisms but not 5-LO.

A Method for the Detection of Meaningful and Reproducible Group Signatures From Gene Expression Profiles

“…Roumestan et al have shown that antihistamines inhibit NF-kappaB through both H1 receptor-dependent and independent mechanisms. 36 This profile does not replicate when compared to the equivalent group (Respiratory Agent: Histamine Antagonist) from the dataset presented by Polymeropoulos et al, though a similar trend is seen. The average number of probes in common is four and one respectively, for the up-and downexpressed signatures (p = 1.13E−03 and p = 3.60E−01).…”

Characterization of Anti-Inflammatory Properties and Evidence for No Sedation Liability for the Novel Antihistamine SUN-1334H

“…Histamine by its action on H 1 receptors has been shown to activate NF-ĸB, an important transcription factor that binds with promoter/enhancer regions of genes regulating production of a number of pro-inflammatory cytokines and adhesion molecules [42]. Antihistamines down-regulate activation of NF-ĸB to inhibit inflammatory cell accumulation and activation [43]. Cetirizine and azelastine have been shown to down-regulate NF-ĸB expression in parallel with inhibition of generation of the cytokines, IL-1β, IL-6, IL-8, TNF-α and GM-CSF [44, 45].…”

Transcriptional microarray analysis reveals suppression of histamine signaling by Kujin alleviates allergic symptoms through down-regulation of FAT10 expression

“…Although no mechanistic explanation was described, suppression of NF-κB by Kujin was reported [29,30]. Activation of NF-κB by histamine through H1R was also reported [19]. We have not examined the effect of Kujin extract on NF-κB activation in the nasal mucosa from TDIsensitized rats.…”

“…Histamine was shown to activate NF-κB through H1R [16][17][18]. Over expression of H1R by histamine led to a significant induction of NF-κB activities and this activity was inhibited by H 1 -antihistamines [19]. Recent study demonstrated the contribution of FAT 10 on NF-κB activation and subsequent expression of NF-κB-regulated genes [20].…”