Kujin Suppresses Histamine Signaling at the Transcriptional Level in Toluene 2,4-Diisocyanate–Sensitized Rats

Abstract

Abstract. Kujin, the dried root of Sophorae flavescensis, has been used in Chinese folklore medicine against allergy. Evaluation of its anti-allergic potential as well as its mechanism of action has rarely been established. We investigated the effect of Kujin on toluene-2,4-diisocyanate (TDI)-induced allergic behavior and related histamine signaling including mRNA levels of histamine H 1 receptor (H1R) and histidine decarboxylase (HDC), H1R and HDC activities, and histamine content in rat nasal mucosa. We also investigated the effect of Kujin on the mRNA levels of helper T cell type 2 (Th2)-cytokine genes closely related to histamine signaling. TDI provocation caused acute allergic symptoms accompanied with up-regulations of H1R and HDC mRNAs and increases in HDC activity, histamine content, and [ 3 H]mepyramine binding activity in the nasal mucosa, all of which were significantly suppressed by pretreatment with Kujin for 3 weeks. Kujin also suppressed the TDI-induced IL-4 and IL-5 mRNA elevations. These data suggest that oral administration of Kujin showed anti-allergic activity through suppression of histamine signaling by the inhibition of TDI-induced H1R and HDC mRNA elevations followed by decrease in H1R, HDC protein level, and histamine content in the nasal mucosa of TDI-sensitized rats. Suppression of Th2-cytokine signaling by Kujin also suggests that it could affect the histamine-cytokine network.

Involvement of Protein Kinase Cδ/Extracellular Signal-regulated Kinase/Poly(ADP-ribose) Polymerase-1 (PARP-1) Signaling Pathway in Histamine-induced Up-regulation of Histamine H1 Receptor Gene Expression in HeLa Cells

“…The H1R expression level is highly correlated to the severity of allergic symptoms, and compounds that suppress H1R gene expression alleviate allergic symptoms (12)(13)(14)(15)(16). Therefore, drugs targeting the proteins that compose the signaling pathway involved in histamine-induced up-regulation of H1R gene expression could be good therapeutics for allergic diseases.…”

“…The strength of H1R signaling depends on the H1R expression level (8). Our recent studies have demonstrated that the level of H1R gene expression is strongly correlated with the severity of allergic symptoms in model rats and patients with pollinosis (9,10), and compounds that suppress H1R gene up-regulation alleviate allergic symptoms (11)(12)(13)(14)(15)(16). These findings suggest that the H1R gene is an allergy-sensitive gene, i.e.…”

Inverse Agonistic Activity of Antihistamines and Suppression of Histamine H1 Receptor Gene Expression

“…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.…”

Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (−)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

“…This Kampo herb has been used extensively in the treatment of allergic diseases and many other pathological conditions for many years in Asian countries. In a previous study, we showed that Kujin extract inhibited up-regulation of H1R and IL-4 gene expression in TDI-sensitized rats (6). We have identified (Ϫ)-maackiain as an antiallergic component in Kujin (14).…”

“…Recently, we reported that the H1R gene expression strongly correlated with the severity of allergic symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats, a commonly used allergy model, and patients with Japanese cedar pollinosis (3,4). We also demonstrated that compounds that suppress up-regulation of H1R gene expression alleviate allergy symptoms (5)(6)(7)(8). These findings strongly suggest that H1R signaling is very important for the development of pollinosis and that drugs targeting H1R signaling will be effective for allergic diseases.…”