Pollinosis is a seasonal allergic rhinitis caused by hypersensitivity to tree or grass pollens, which affects more than 36 million people in the U.S. and about 16% of the Japanese population (1, 2). Histamine is a major chemical mediator involved in allergic reactions. Its actions are mainly mediated by the histamine H 1 receptor (H1R) and H1R activation results in the symptoms of allergic rhinitis.It has been reported that expression of H1R mRNA is increased in patients with allergic rhinitis (3,4). We have demonstrated that intranasal application of toluene-2,4-diisocyanate (TDI) induces histamine release from mast cells via neurogenic inflammation and causes nasal hypersensitivity in rats (5), with H1R expression being up-regulated at both the mRNA and protein levels in the nasal mucosa of TDI-sensitized rats (6). We have also demonstrated that the level of H1R expression is strongly correlated with the severity of allergy symptoms in TDIsensitized rats and in patients with pollinosis (7), while agents that suppress H1R gene up-regulation alleviate allergy symptoms (8, 9). These findings, combined with the report that the strength of H1R signaling depends on the level of expression of this receptor (10), suggest that H1R is an allergy-sensitive gene and that its expression influences the severity of allergy symptoms. Therefore, drugs targeting the signaling pathway involved in histamine-induced up-regulation of H1R gene expression could be useful for treating allergic diseases.Antihistamines are widely employed as the first-line treatment for nasal symptoms of pollinosis because these drugs are thought to antagonize histamine and prevent it from binding to the H1R. According to the two-state model, however, the active and inactive states of a receptor exist in equilibrium, so antihistamines could act as inverse agonists that combine with and stabilize the inactive form of H1R to shift the equilibrium toward the inactive state and down-regulate constitutive receptor activity, even in the absence of histamine (11). Therefore, antihistamines might not only antagonize histamine by blocking its binding with the H1R, but could also suppress constitutive H1R activity. Although the clinical importance of constitutive activity has not been clarified, it can be hypothesized that inverse agonists would more potently alleviate allergic symptoms than neutral antagonists by inhibiting constitutive activity. However, the influence of the inverse agonistic activity of antihistamines on H1R gene expression has not been evaluated.We previously demonstrated that histamine stimulates up-regulation of H1R gene expression in HeLa cells that endogenously express this receptor (6). In the present study, we examined the effect of inverse agonists on upregulation of H1R gene expression by HeLa cells. Our Tokushima 770-8505, Japan Received September 29, 2011; Accepted November 15, 2011 Abstract. Histamine H 1 receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R g...
Histamine H1 receptor (H1R) gene is up-regulated in patients with allergic rhinitis, and its expression level strongly correlates with the severity of symptoms. However, the mechanism underlying this remains unknown. Here we report the mechanism of H1R gene up-regulation. The luciferase assay revealed the existence of two promoter regions, A and B1. Two AP-1 and one Ets-1 bound to region A, while Ku86, Ku70, and PARP-1 bound to region B1. Ku86 was responsible for DNA binding and poly(ADP-ribosyl)ated in response to phorbol-12-myristate-13-acetate stimulation, inducing its dissociation from region B1 that is crucial for promoter activity. Knockdown of Ku86 gene enhanced up-regulation of H1R gene expression. Experiments using inhibitors for MEK and PARP-1 indicate that regions A and B1 are downstream regulatory elements of the PKCδ/ERK/PARP-1 signaling pathway. Data suggest a novel mechanism for the up-regulation of H1R gene expression.
p40 phox activated phagocyte NADPH oxidase without p47 phox in a cell-free system consisting of p67 phox , Rac and cytochrome b 558 relipidated with phosphatidylinositol 3-phosphate. The activation reached to 70% of that by p47 phox . Addition of p47 phox slightly increased the activation, but not additively. p40 phox improved the efficiency of p67 phox in the activation. The C-terminus-truncated p67 phox , p40 phox (D289A), p40 phox (R58A), or p40 phox (W207R) showed an impaired activation. A peptide corresponding to the p22 phox Pro-rich region suppressed the activation, and far-western blotting revealed its interaction with p40 phox SH3 domain. Thus, p40 phox can substitute for p47 phox in the activation, interacting with p22 phox and p67 phox through their specific regions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.