The cross-regulation between H1 and H2 histamine receptors modulates the behavior of H2 receptor blockers

SAHORES A; BURGHI V; FERNANDEZ NC; DIAZ NEBREDA A; RODRIGUEZ A; DAVIO C; ZAPPIA CD; MONCZOR F; SHAYO C

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Histamine, modulates several biological processes, including allergy and gastric acid secretion, through H1 and H2 receptors. H2 blockers (H2B) are mainly used to treat gastrointestinal disorders, and much interest is focused on their repositioning for other pathologies. For it, deep understanding of their mechanisms of action is needed. We have previously described that H1 and H2 agonists (H1A and H2A) induce the receptor?s co-internalization and cross-desensitization. We have also reported that H2B lead to desensitization and internalization of H2 receptor. Now, we hypothesize that H2B may also induce H1 receptor?s cross-desensitization and co-internalization and that the cross-regulation induced by H1A will affect the behavior of H2B. In HEK293 cells transfected with both receptors (HEK-H1-H2), pretreatment with the H2B (cimetidine, ranitidine and famotidine) significantly reduced the activation of H1 receptor, evaluated through IL-6 promoter´s activity. Similar results were obtained for COX-2 and IL-8 gene expression, by qPCR in U937 cells. Also, we analyzed the impact of H2B in the antiproliferative/apoptotic response induced by H1A. Proliferation, cell cycle and annexin V assays showed that H2B reduced the antiproliferative/apoptotic response induced by H1A. Regarding the effect of H1 receptor activation on H2B response, H1A prevented the reduction of cAMP levels induced by H2B, in U937 and HEK-H1-H2 cells. Additionally, saturation-binding assays showed that H2B lead to a decrease in H1 receptor binding sites. Finally, we analyzed the cross-regulation induced by H2B in presence of the receptor internalization inhibitor, dynasore. In this condition, none of the H2B used were able to modify the IL-6 promoter´s activity induced by H1A. This indicates that the co-internalization process is responsible of the cross-regulation induced by H2B. Our study provides new insights in the mechanisms of action of H1 and H2 receptors that explain the effect of antihistamines and opens up new venues for novel therapeutic applications.