H1 and H2 histamine receptor cross-desensitization affects antihistamine response.

ZAPPIA C; FERNANDEZ NC; DIAZ NEBREDA, A; MONCZOR F; RODRIGUEZ-GONZALEZ A; SHAYO C

Buenos Aires

Congreso; Reunión Conjuntas de Sociedades de Biociencias; 2017

SAIC

Histamine exerts its effects by binding to four G protein-coupled receptors (H1R-H4R). Histamine modulates numerous physiopathological processes through H1R and H2R, including allergy and inflammation. These receptors are effectively targeted with approved drugs for human treatment which belong to the top twenty-used-drug-classes. We have previously described a 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 different AH and its 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, the pretreatment with mepyramine, trans-triprolidine, chlorpheniramine and diphenhydramine significantly decreased the cAMP production following amthamine (AM, an H2R agonist) stimulation, whereas the cAMP response through another Gs-coupled receptor (PGE2) was unaffected. Likewise, the pretreatment with AH in HEK cells transfected 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-inflammatory response in HEK cells transfected with H1R. These results show that there is a specific cross-desensitization between H1R and H2R induced by different AH used in the clinic. Given the wide use of these drugs and the interest in drugs repositioning, it is crucial to understand the regulation between the intracellular signaling cascades triggered by them.