Abstract
Histamine H1 receptor (H1R) is one of the targets of histamine in the nervous system and the peripheral tissues. Protein kinase Cδ (PKCδ) signaling is involved in histamine-induced upregulation of H1R gene expression in HeLa cells. Histamine also upregulates H1R gene expression in U-373 MG cells. However, the molecular signaling of this upregulation is still unclear. Here, we investigated the molecular mechanism of histamine-induced H1R gene upregulation in U-373 MG cells. Histamine-induced H1R gene upregulation was inhibited by H1R antagonist d-chlorpheniramine, but not by ranitidine, ciproxifan, or JNJ77777120, and H2R, H3R, or H4R antagonists, respectively. Ro-31-8220 and Go6976 also suppressed this upregulation, however, the PKCδ selective inhibitor rottlerin and the PKCβ selective inhibitor Ly333531 did not. Time-course studies showed distinct kinetics of H1R gene upregulation in U-373 MG cells from that in HeLa cells. A promoter assay revealed that the promoter region responsible for H1R gene upregulation in U-373 MG cells was different from that of HeLa cells. These data suggest that the H1R-activated H1R gene expression signaling pathway in U-373 MG cells is different from that in HeLa cells, possibly by using different promoters. The involvement of PKCα also suggests that compounds that target PKCδ could work as peripheral type H1R-selective inhibitors without a sedative effect.
Highlights
Histamine is involved in physiological and pathological functions in both peripheral tissue and the nervous system, and its actions are mediated by four histamine receptor subtypes, H1, H2, H3, and H4 receptors [1,2]
We have shown that prophylactic administration of antihistamines decreased nasal mucosal H1 receptor (H1R) gene upregulation with alleviation of nasal symptoms in patients with pollinosis [9]
Our data revealed that histamineinduced upregulation of H1R gene expression in U-373 MG cells is mediated by H1R
Summary
Histamine is involved in physiological and pathological functions in both peripheral tissue and the nervous system, and its actions are mediated by four histamine receptor subtypes, H1 , H2 , H3 , and H4 receptors [1,2]. By using environmental exposure units, we showed that pre-administration of ebastine, an antihistamine, downregulated H1R gene expression before pollen exposure and inhibited polleninduced nasal symptoms and pollen-induced upregulation of H1R gene expression in the nasal mucosa of patients with pollinosis [10]. These findings suggest that the H1R gene is an allergy-sensitive gene, i.e., its expression level affects the severity of symptoms, and compounds that target the H1R gene expression pathway might be useful for developing new effective anti-allergic medications. Stimulation with histamine caused a rapid and transient increase in the H1R mRNA level in U-373 MG cells, which is different from that in HeLa cells, suggesting that H1R gene transcription was regulated by the different promoter from that in HeLa cells
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