Abstract
Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat inflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with the high morbidity levels of such inflammatory conditions, these receptors are the targets of a vast number of approved drugs, and in many situations their ligands are co-administered. However, this drug association has no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling could affect GR-mediated activity, impacting on its transcriptional outcome. Indeed, our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-protein βγ subunits and a parallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamine and clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation and transrepression in a gene-specific manner. Our work provides a delineation of molecular mechanisms underlying the widespread clinical association of antihistamines and GR agonists, which may contribute to future dosage optimization and reduction of well-described side effects associated with glucocorticoid administration.
Highlights
Human HEK293T cells were co-transfected with a luciferase reporter plasmid under the control of a synthetic promoter regulated by the glucocorticoid receptor (GR) (TAT3-Luc) in combination with plasmids coding for GR and H1 receptor (H1R) and cells were stimulated with dexamethasone
While 100 μ M histamine induced no significant effect on luciferase activity, the addition of 100 μ M histamine 10 min prior to a 24 h dexamethasone treatment induced a two-fold increment in maximal luciferase activity induced by dexamethasone alone (2923 ± 1 69 vs. 6201 ± 3 44, both expressed in luminescence arbitrary units) without affecting dexamethasone’s pEC50 (11.58 ± 0 .15 vs. 11.61 ± 0 .15) (Fig. 1A)
These results indicate that G-protein dependent intracellular signaling triggered by histamine-mediated activation of the H1R potentiates GR transcriptional activity induced by synthetic and natural GR agonists
Summary
Add-on therapies present another way to control adverse effects by reducing GC dose and combining it with a different drug with anti-inflammatory activity. It has been accepted that GC’s anti-inflammatory activity may be due to GR interaction with transcription factors, e.g. NF-κ B, and inhibition of gene expression (transrepression), while the activation of gene transcription by GR binding to GREs (transactivation) may be responsible of metabolic effects and adverse effects at pharmacological doses[6,8,9]. Since histamine pro-inflammatory effects are largely mediated by its action on H1R, antagonists of this receptor are often used to treat several inflammatory-related conditions Many of these clinically used antihistamines are not antagonists but inverse agonists, decreasing H1 receptor constitutive activity[12,13]. The characterization of signaling mechanisms underlying these complex interactions, as well as the discussion of their possible clinical implications, are the main purpose of the present work
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