Histamine H₁ Receptor Gene as an Allergic Diseases-sensitive Gene and Its Impact on Therapeutics for Allergic Diseases

Abstract

Therapeutics targeting disease-sensitive genes are required for the therapy of multifactorial diseases. There is no clinical report on therapeutics for allergic disease-sensitive genes. We are focusing on the histamine H 1 receptor (H1R) as a sensitive gene. H1R mediates allergy histamine signals. H1R is a rate-limiting molecule of the H1R signal because the signal is increased with elevated receptor expression level. We discovered that the stimulation of H1R induced H1R gene expression through PKCd activation, resulting in receptor upregulation. The mechanism of H1R gene expression was revealed to play a key role in the receptor expression level in studies using cultured HeLa cells and allergic rhinitis model rats. Preseasonal prophylactic treatment with antihistamines is recommended for the therapy of pollinosis. However, the mechanism of the therapy remains to be elucidated. We demonstrated that repeated pretreatment treatment with antihistamines in the allergic rhinitis model rats resulted not only in improvement of symptoms but also in suppressed elevation of H1R mRNA levels in the nasal mucosa. A clinical trial was then initiated. When symptoms and H1R mRNA levels in the nasal mucosa of pollinosis patients with or without preseasonal prophylactic treatment with antihistamines were examined, both symptoms and high levels of H1R mRNA were signiˆcantly improved in treated compared with untreated patients. These results strongly suggest that H1R is an allergic disease-sensitive gene.

H1 antihistamines in allergic rhinitis: The molecular pathways of interleukin and toll - like receptor systems

“…Therefore, H1-antihistamines can reduce the proinflammatory cell expression and accumulation of eosinophils and neutrophils (18). It has been showed that the expression of the H1-histamine receptor affects the severity of AR and that the expression of the H1-histamine receptor messenger ribonucleic acid (mRNA) in AR is increased (9). In addition, upregulation of the H1-histamine Several studies reported the association of AR with IL-4 gene polymorphisms in ethnically and geographically distinct populations.…”

“…This process is determined by the variation in gene expression. Study by Mizuguchi et al (9) showed that the variation in cytokine receptor genes and H1-histamine receptors played an important role in the pathogenesis of AR. Hussein et al (10) showed that polymorphisms of Toll-like receptors 2 (TLR-2) and TLR-4 genes were associated with susceptibility to AR.…”

Histamine Receptors as Potential Therapeutic Targets for Cancer Drug Development

“…H 1 R also activates NF-kB through G q11 and G upon agonist binding, while constitutive activation of NF-kB occurs only through the G (Bakker et al, 2001;Leurs et al, 1995;Smit et al, 1999). Recently, it was reported that the stimulation of H 1 R induced H 1 R gene expression through protein kinase C (PKC ) activation, resulting in receptor upregulation (Mizuguchi et al, 2011). …”