H1 and H2 histamine receptors cross-desensitization affects antihistamine response

Abstract

Histamine exerts its effects by binding to four G protein-coupled receptors (H1R-H4R) and modulates numerous physiopathological processes through H1R and H2R, including allergy and inflamma- tion. These receptors are effectively targeted by drugs belonging to the top twenty-used-drug-classes. We have previously described the cross-desensitization (CDS) between both receptors induced by Cetirizine, an H1R antihistamine (AH), on H2R agonist response. The aim of this work is to study the CDS between H1R and H2R caused by others AH and their influence on the regulation of the inflammatory process. In promonocytic U937 cells (endogenously expressing H1R and H2R) and HEK293 (HEK) cells transfected with H1R and H2R, pretreatment with the AHs mepyramine, trans-tripro- lidine, chlorpheniramine and diphenhydramine significantly de- creased the cAMP production following amthamine (AM, an H2R agonist) stimulation, whereas the cAMP response through another Gs-coupled receptor (PGE2) was unaffected. Likewise, the pretreat- ment with the same AHs in HEK cells transfected only with H2R, did not alter AM response, showing specificity of CDS. On the other hand, we evaluated the AM effect on the inflammatory response of AH. The regulation of COX-2 and IL-8 expression was evaluated by qPCR in U937 cells treated with PMA. The pretreatment with AM reverted the inhibitory effects of the AH on the expression of both genes. The same effect was observed for the IL6 promoter activity in HEK cells transfected with both receptors in a reporter gene assay. As expected, the pretreatment with AM did not modify the AH anti-in- flammatory response in HEK cells transfected only with H1R. These results show that there is a specific cross-desensitization between H1R and H2R induced by different AHs used in the clinic. Given the wide use of these drugs and the interest in drug repositioning, it is crucial to understand the regulation between the intracellular signal- ing cascades triggered by them.