Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells (35.10)

Abstract

Abstract Histamine (HIS) is a well-recognized modulator of vascular inflammation. We have shown that HIS, acting via H1 receptors (H1R), synergizes LPS-induced production of IL-6, IL-8, PGE2 and PGI2 by endothelial cells. The synergy between HIS and LPS was partly attributed to HIS-induced expression of TLR4. In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) and enhances HIS responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in 2- to 4-fold increases in H1R mRNA expression in a time and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. LPS-induced H1R expression was maximum at 4h after LPS treatment which returned to the basal level by 8h. The LPS-induced H1R gene expression was mediated through TLR4 because gene silencing by TLR4-siRNA inhibited LPS effect. The specific binding of [3H]-pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was 3-fold higher than the untreated cells. When HCAEC were pretreated with LPS for 24h, washed and subsequently challenged with HIS, 15-, 17- and 10-fold increases in IL-6, PGI2 and PGE2 production, respectively, were noted. HIS-induced syntheses of IL-6, PGE2 and PGI2 by LPS-primed HCAEC were completely blocked by the H1R antagonist cetirizine. These results demonstrate that LPS upregulates the expression and function of H1R in HCAEC leading to agonist-induced increase in IL-6, PGI2 and PGE2 production.