Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways

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.

Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model

“…We first validated that AZE had similar effect on DEX‐induced GR transcriptional activity in vitro , as previously reported for the antihistamines mepyramine and triprolidine . HEK293T cells were cotransfected with a luciferase encoding plasmid under the control of a synthetic promoter regulated by the GR (TAT3‐Luc) in combination with plasmids encoding for GR and H 1 receptor.…”

“…As shown before, no differences were observed in results normalized to Renilla-Luc or to protein expression levels. 4 EXP-FYB N° 0040903/2015) and were performed in accordance with institutional and national guidelines for animal protection. Animal studies are reported in compliance with the ARRIVE guidelines.…”

“…We have previously reported that antihistamines, acting on the histamine H 1 receptor, are capable of enhancing the transcriptional activity of the glucocorticoid receptor (GR), an effect that could have clinical relevance, particularly for inflammation‐associated conditions. Importantly, the GR and the H 1 receptor are the targets of the largest number of drugs currently approved for clinical treatment .…”

“…effect mediated by a Gαq-PLC pathway. Activation of the H 1 receptor by its full agonists resulted in a composite potentiating effect.Intriguingly, inactivation of the Gαq-PLC pathway by H 1 receptorinverse agonists (ie, mepyramine and triprolidine) resulted also in a potentiation of GR activity 4. This was observed in heterologous expression systems, through gene-reporter assays and measuring the expression of endogenous inflammatory-related genes in physio-pathological cell models 4.…”

Therapeutic utility of glucocorticoids and antihistamines cotreatment. Rationale and perspectives

“…This clinical practice has been stablished based on the assumption that there should be an intrinsic benefit in their coadministration due to their antiinflammatory effects. 26 It has been shown that the combination of antihistamines and corticoids is the most widely used choice to treat all types of AR. 27 Several clinical trials have shown the benefits of the combination of the antihistamine azelastine (AZE) and the corticoid fluticasone (FLU), resulting in the patent granting of the first steroid plus antihistamine nasal spray (Dymista®) along with two other steroid combinations.…”