H1 And H2 Histamine Receptors Cross-Desensitization Affects Antihistamine Response

RODRIGUEZ A; SHAYO C; DÍAZ NEBREDA A; MONCZOR F; ZAPPIA C D; FERNANDEZ NATALIA

Mar del Plata

Congreso; Reunion Conjunta de Sociedades de Biociencias: LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), SAIB, SAI, SAA, SAB, SAB, SAFE, SAFIS, SAH, SAP.; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Histamine exerts its effects by binding to four G protein-coupledreceptors (H1R-H4R) and modulates numerous physiopathologicalprocesses through H1R and H2R, including allergy and inflammation.These receptors are effectively targeted by drugs belonging tothe top twenty-used-drug-classes. We have previously describedthe cross-desensitization (CDS) between both receptors induced byCetirizine, an H1R antihistamine (AH), on H2R agonist response.The aim of this work is to study the CDS between H1R and H2Rcaused by others AH and their influence on the regulation of theinflammatory process. In promonocytic U937 cells (endogenouslyexpressing H1R and H2R) and HEK293 (HEK) cells transfected withH1R and H2R, pretreatment with the AHs mepyramine, trans-triprolidine,chlorpheniramine and diphenhydramine significantly decreasedthe cAMP production following amthamine (AM, an H2Ragonist) stimulation, whereas the cAMP response through anotherGs-coupled receptor (PGE2) was unaffected. Likewise, the pretreatmentwith the same AHs in HEK cells transfected only with H2R,did not alter AM response, showing specificity of CDS. On the otherhand, we evaluated the AM effect on the inflammatory response ofAH. The regulation of COX-2 and IL-8 expression was evaluated byqPCR in U937 cells treated with PMA. The pretreatment with AMreverted the inhibitory effects of the AH on the expression of bothgenes. The same effect was observed for the IL6 promoter activity inHEK cells transfected with both receptors in a reporter gene assay.As expected, the pretreatment with AM did not modify the AH anti-inflammatoryresponse in HEK cells transfected only with H1R. Theseresults show that there is a specific cross-desensitization betweenH1R and H2R induced by different AHs used in the clinic. Given thewide use of these drugs and the interest in drug repositioning, it iscrucial to understand the regulation between the intracellular signalingcascades triggered by them.