β‐eudesmol suppresses allergic reactions via inhibiting mast cell degranulation

The regulatory effect of β‐eudesmol, which is an active constituent of Pyeongwee‐San (KMP6), is evaluated for allergic reactions induced by mast cell degranulation. Phorbol 12‐myristate 13‐acetate (PMA) plus calcium ionophore A23187‐stimulated human mast cell line, HMC‐1 cells, and compound 48/80‐stimulated rat peritoneal mast cells (RPMCs) are used as the in vitro models; mice models of systemic anaphylaxis, ear swelling, and IgE‐dependent passive cutaneous anaphylaxis (PCA) are used as the in vivo allergic models. The results demonstrate that β‐eudesmol suppressed the histamine and tryptase releases from the PMA plus calcium ionophore A23187‐stimulated HMC‐1 cells. β‐eudesmol inhibits the expression and activity of histidine decarboxylase in the activated HMC‐1 cells. In addition, β‐eudesmol inhibits the levels of histamine and tryptase released from the compound 48/80‐stimulated RPMCs. Furthermore, β‐eudesmol decreases the intracellular calcium level in the activated RPMCs. β‐eudesmol also decreases the compound 48/80‐induced mortality and ear swelling response. β‐eudesmol suppresses the serum levels of histamine, IgE, interleukin (IL)‐1β, IL‐4, IL‐5, IL‐6, IL‐13, and vascular endothelial growth factor (VEGF) under PCA mice as well as PCA reactions. Therefore, the results from this study indicate the potential of β‐eudesmol as an anti‐allergic drug with respect to its pharmacological properties against mast cell‐mediated allergic reactions.     

Magnoliae flos inhibits mast cell-dependent immediate-type allergic reactions.

The mast cell plays a pivotal role in initiating allergic response by secreting intracytoplasmic granular mediators such as histamine. Magnoliae flos has been used for the treatment of allergic disease in Korea. However, its effect in experimental models remains unknown. The present report describes an inhibitory effect of Magnoliae flos on mast cell-mediated immediate-type allergic reactions. Topical application of compound 48/80 can induce an ear swelling response in normal (WBB6F1-+/+) mice but not in the congenic mast cell-deficient WBB6F1-W/Wv mice. Magnoliae flos inhibited concentration-dependently mast cell-dependent ear swelling response induced by compound 48/80 by topical application. Magnoliae flos inhibited concentration-dependently passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) IgE in rats by topical application. Magnoliae flos also inhibited concentration-dependently the histamine release from the rat peritoneal mast cells by compound 48/80 or anti-DNP IgE. Moreover, Magnoliae flos had a significant inhibitory effect on compound 48/80-induced systemic anaphylactic reaction. These results indicate that Magnoliae flos inhibits immediate-type allergic reactions by inhibition of mast cell degranulation in vivo and in vitro.     

Effect of Sinpo-Tang on the mast cell-mediated anaphylactic reactions.

The herbal formulation Sinpo-Tang (SPT) has long been used for various allergic diseases. We investigated the effect of SPT on the mast cell-mediated anaphylactic reactions in vivo and in vitro murine models. SPT dose dependently inhibited compound 48/80-induced ear swelling response and histamine release. SPT (0.001-0.1g/kg) significantly inhibited passive cutaneous anaphylaxis (PCA). The mast cell number was markedly decreased at the SPT-treated PCA site. In addition, SPT decreased intracellular calcium levels of activated mast cells. These results suggest that SPT inhibit the anaphylactic degranulation of mast cells through decrease of the intracellular calcium level.     

Inhibitory effects of Houttuynia cordata water extracts on anaphylactic reaction and mast cell activation

The present study was investigated the effect of Houttuynia cordata THUNB water extract (HCWE) on mast cell-mediated anaphylactic reactions. The mast cell-mediated anaphylactic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. HCWE has been used as a traditional medicine in Korea and is known to have an antioxidant and anti-cancer activities. However, its specific effect of mast cell-mediated anaphylactic reactions is still unknown. We examined whether HCWE could inhibit compound 48/80-induced systemic anaphylaxis, IgE-mediated passive cutaneous anaphylaxis (PCA), and mast cell activation. The oral administration of HCWE inhibited compound 48/80-induced systemic anaphylaxis in mice. HCWE also inhibited the local allergic reaction, PCA, activated by anti-dinitrophenyl (DNP) IgE antibody in rats. HCWE reduced the compound 48/80-induced mast cell degranulation and colchicine-induced deformation of rat peritoneal mast cells (RPMC). Moreover, HCWE dose-dependently inhibited histamine release and calcium uptake of RPMC induced by compound 48/80 or anti-DNP IgE. HCWE increased the level of intracellular cAMP and inhibited significantly the compound 48/80-induced cAMP reduction in RPMC. These results suggest that HCWE may be beneficial in the treatment of mast cell-mediated anaphylactic responses.     

Inhibition of anaphylaxis-like reaction and mast cell activation by water extract from the fruiting body of Phellinus linteus

Mast cell-mediated anaphylactic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. Phellinus linteus has been used as a traditional herb medicine in oriental countries and is known to have anti-tumor, immunomodulatory, anti-inflammatory, and anti-allergic activities. However, roles of Phellinus linteus in the mast cell-mediated anaphylactic reactions have not fully been examined. In the present study, we have investigated the effects of water extract from the fruiting body of Phellinus linteus (WEPL) on mast cell-mediated anaphylaxis-like reactions. Oral administration of WEPL inhibited the compound 48/80-induced systemic anaphylaxis-like reaction and ear swelling response. WEPL also inhibited the anti-dinitrophenyl (DNP) IgE-mediated passive systemic and cutaneous anaphylaxis. WEPL had no cytotoxicity on rat peritoneal mast cells (RPMC). WEPL dose-dependently reduced histamine release from RPMC activated by compound 48/80 or anti-DNP IgE. Moreover, WEPL decreased the compound 48/80-induced calcium uptake into RPMC. Furthermore, WEPL increased the level of intracellular cAMP and significantly inhibited the compound 48/80-induced cAMP reduction in RPMC. These results suggest that WEPL may serve as an effective therapeutic agent for allergic diseases.     

Inhibitory effect of mast cell-mediated immediate-type allergic reactions by Cichorium intybus.

We investigated the effect of an aqueous extract of Cichorium intybus (CIAE) on mast cell-mediated immediate type allergic reactions. CIAE (0.1-1000 mg kg-1) dose-dependently inhibited systemic anaphylactic reaction induced by compound 48/80 in mice. Especially, CIAE inhibited compound 48/80-induced anaphylactic reaction 100% with the dose of 1000 mg kg-1. CIAE 1000 mg kg-1also significantly inhibited local anaphylactic reaction activated by anti-dinitrophenyl (DNP) IgE. When mice were pretreated with CIAE at a concentration ranging from 0.1 to 1000 mg kg-1, the plasma histamine levels were reduced in a dose-dependent manner. CIAE (1-1000 microg ml-1) dose-dependently inhibited histamine release from the rat peritoneal mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. The level of cAMP in RPMC, when CIAE (1000 microg ml-1) was added, increased significantly compared with that of control cells. These results indicate that CIAE inhibits mast cell-mediated immediate-type allergic reactions in vivo and in vitro.     

Pharmacological study on citrus fruits. II. Anti-allergic effect of fruit of Citrus unshiu MARKOVICH (2). On flavonoid components]

A study was carried out to clarify the active component of green fruit of Citrus unshiu MAKOVICH on the type I allergic reaction. The flavonoid component, isolated from its methanolic extract, hesperidin, was found to inhibit histamine release from peritoneal mast cells of rats induced by compound 48/80. Forty eight-hour homologous passive cutaneous anaphylaxis (PCA) in intact rats was significantly inhibited by the oral administration of hesperidin. However, the anti-allergic action on PCA was not observed in adrenalectomized rats. These results suggests that hesperidin is an effective component of the fruit of Citrus unshiu with the anti-allergic action against the type I reaction.     

Lavender oil inhibits immediate-type allergic reaction in mice and rats

We studied the effects of lavender oil on mast cell-mediated immediate-type allergic reactions in mice and rats. Lavender oil (1:500, 1:100, 1:10, 1:1, 1:0) inhibited concentration-dependently mast cell-dependent ear swelling response induced by compound 48/80 in mice by both topical and intradermal application. Lavender oil (1:500, 1:100, 1:10, 1:1, 1:0) inhibited concentration-dependently passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) IgE in rats by both topical and intradermal application. Lavender oil (1:500, 1:100, 1:10, 1:1, 1:0) also inhibited concentration-dependently the histamine release from the peritoneal mast cells by compound 48/80 or anti-DNP IgE. Moreover, lavender oil (1:1000, 1:100, 1:10, 1:0) had a significant inhibitory effect on anti-DNP IgE-induced tumour necrosis factor-alpha secretion from peritoneal mast cells. These results indicate that lavender oil inhibits immediate-type allergic reactions by inhibition of mast cell degranulation in-vivo and in-vitro.     

Association between perfluorooctanoic acid exposure and degranulation of mast cells in allergic inflammation

Perfluorooctanoic acid (PFOA) has wide applications, including as a raw material for converted paper and packaging products. With the widespread use of PFOA, concerns regarding its potential environmental and health impacts have increased. In spite of the known hepatotoxicity and genotoxicity of PFOA, correlation with PFOA and allergic inflammation is not well known. In this study, the effect of PFOA on the degranulation of mast cells and mast cell‐mediated allergic inflammation in the presence of FcεRI cross‐linking was evaluated. In immunoglobulin (Ig) E‐stimulated mast cells, PFOA increased the release of histamine and β‐hexosaminidase by the up‐regulation of intracellular calcium levels. PFOA enhanced gene expression of several pro‐inflammatory cytokines, including tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, and IL‐8 by the activation of nuclear factor (NF)‐κB in IgE‐stimulated mast cells. Also, PFOA exacerbated allergic symptoms via hypothermia, and an increase of serum histamine, TNF‐α, IgE and IgG₁ in the ovalbumin‐induced systemic anaphylaxis. The present data indicate that PFOA aggravated FcɛRI‐mediated mast cell degranulation and allergic symptoms. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen) on experimental allergic reactions

The effects of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen), a new anti-inflammatory agent, on experimental allergic reaction and antibody formation were examined. The action was compared with those of ketoprofen, ibuprofen, indomethacin, tranilast, chlorpheniramine, prednisolone and/or cyclophosphamide. Suprofen inhibited homologous PCA in rats, immunological histamine release from rat peritoneal mast cells and guinea pig lung tissues, Forssman cutaneous vasculitis (FCV) and the Arthus reaction in guinea pigs. The potency for inhibition of the PCA reaction was similar to that of ketoprofen and more potent than ibuprofen and trailast. As for the release of anaphylactic mediators, suprofen was less potent than tranilast in terms of histamine release, but not the release of the slow reacting substance of anaphylaxis (SRS-A). Suprofen inhibited FCA more potently than other nonsteroidal anti-inflammatory drugs (NSAID). The inhibition of the Arthus reaction by suprofen was similar to those of other NSAID and prednisolone. Suprofen hardly affected delayed hypersensitivity in guinea pigs and antibody (IgM or IgE) formation in mice or rats.     

Inhibitory effects of Agaricus blazei on mast cell-mediated anaphylaxis-like reactions

Agaricus blazei is a medicinal mushroom native to Brazil. It used to be a source of anti-tumor and immunmoactive compounds and considered a health food in many countries. However, its specific effect against mast cell-mediated anaphylactic reactions is still unknown. In the present study, we investigated the effect of Agaricus blazei water extract (ABWE) on mast cell-mediated anaphylaxis-like reactions. We examined whether ABWE could inhibit systemic anaphylaxis-like reaction, ear swelling response, passive cutaneous anaphylaxis, and mast cell activation. ABWE inhibited compound 48/80-induced systemic anaphylaxis-like reaction, ear swelling response, and passive cutaneous anaphylaxis-like reaction in mice. ABWE also inhibited anti-dinitrophenyl (DNP) IgE-mediated passive cutaneous anaphylaxis. ABWE dose-dependently inhibited compound 48/80-induced or anti-DNP IgE-mediated histamine release from rat peritoneal mast cells (RPMC). Moreover, pretreatment with ABWE reduced compound 48/80-induced calcium uptake into RPMC. When ABWE was added, the level of intracellular cAMP in RPMC showed a significant increase compared with that of control cells. In addition, ABWE significantly inhibited compound 48/80-induced cAMP reduction in RPMC. These results propose that ABWE may be beneficial in the treatment of mast cell-mediated anaphylactic reactions.     

Inhibitory effects of Morus alba on compound 48/80-induced anaphylactic reactions and anti-chicken gamma globulin IgE- mediated mast cell activation

We investigated the effects of hot-water extract from the root bark of Morus alba (HEMA) on anaphylactic reactions. Using in vitro and in vivo experiments, we examined whether HEMA could inhibit compound 48/80-induced systemic anaphylactic shock and anti-chicken gamma globulin (CGG) IgE-mediated rat peritoneal mast cell activation. HEMA significantly inhibited systemic anaphylaxis induced by the compound 48/80 in mice. HEMA also significantly inhibited the passive cutaneous anaphylaxis activated by anti-CGG IgE. HEMA had no cytotoxicity on rat peritoneal mast cells (RPMC). Moreover, HEMA dose-dependently inhibited mast cell degranulation, histamine release and calcium uptake into RPMC induced by the compound 48/80 or anti-CGG IgE. When HEMA was added, the level of intracellular cAMP in RPMC showed a transient and significant increase (5-fold) compared with that of control cells. HEMA also inhibited significantly the compound 48/80-induced cAMP reduction in RPMC. These results suggested that HEMA inhibits the compound 48/80- or anti-CGG IgE-induced mast cell activation and its inhibitory effects on mast cell activations were favorably comparable to disodium cromoglycate. And HEMA is a candidate for effective therapeutic tools of allergic diseases.     

Immunopharmacological study of buckwheat hypersensitivity (author's transl)]

Effect of dialysate from buckwheat extract on immediate hypersensitivity reactions. To investigate the hypersensitivity reaction of buckwheat, the aqueous extract of buckwheat was separated into dialysate (BWD) and non-dialysate (BWND). BWD neither decreased a release of anaphylactic mediator from the chopped lung tissue nor inhibited Schultz-dale reaction in the ileum of guinea pig sensitized with BWND. Heterologous PCA mediated by rabbit anti-BWND serum in guinea pig and homologous PCA in rats using anti-BWND IgE serum were inhibited by i.d. or i.v. treatment of BWD. Radioallegosorbent test (RAST) and PK reaction were inhibited in a dose dependent fashion by BWD mixed with human serum sensitive to buckwheat, although BWD required approximately 10,000 times more than BWND to produce a RAST inhibition. RAST, however, was not affected when BWD was added to 125I-labelled anti-human IgE. Anti-buckwheat IgE antibody in sensitized animals and atopic patients was specifically absorbed with an insoluble copolymer of BWD-conjugated BSA. BWD did not form a precipitin line against anti-BWND IgG antibody in immunoelectrophoresis. Rat IgE serum-induced degranulation and histamine release from mast cells were inhibited in a dose dependent fashion by BWD and the inhibition was specific to anti-BWND IgE antibody. BWD may be useful as an hyposensitization agent in buckwheat hypersensitivity, since BWD is a haptenic substance capable of neutralizing specific IgE antibody on mast cells.     

Inhibition of immunologic and nonimmunologic stimulation-mediated anaphylactic reactions by water extract of white eggplant (Solanum melongena).

We investigated the effect of water extract of Solanum melongena(SMWE) on immunologic and nonimmunologic stimulation-mediated anaphylactic reactions. Nonimmunologic anaphylactic reaction was induced by compound 48/80 injection. Oral administration of SMWE (1 g kg(-1)) completely inhibited compound 48/80-induced anaphylactic reaction. Immunologic anaphylactic reaction was generated by sensitizing the skin with anti-dinitrophenyl (DNP) IgE followed 48 h later with an injection of antigen. Oral administration of SMWE (0.01--1 g kg(-1)) significantly inhibited passive cutaneous anaphylactic reaction activated by anti-DNP IgE to between 83.10 +/- 1.67% and 70.17 +/- 2.17%. SMWE (0.01--1 mg ml(-1)) also inhibited histamine release activated by compound 48/80 to between 93 +/- 2.65 and 70 +/- 1.50%. Moreover, SMWE (0.01--1 mg ml(-1)) had a significant inhibitory effect on IgE-induced tumor necrosis factor (TNF)-alpha secretion from rat peritoneal mast cells. These results indicate that SMWE inhibits immunologic and nonimmunologic stimulation-mediated anaphylactic reactions and TNF-alpha secretion from mast cells.     

Anti-allergic activity of 7-acetyl-5-oxo-5H-[1] benzopyrano (2,3-b] pyridine (Y-9000) (author's transl)]

The IgE mediated reactions such as 48 hr homologous passive cutaneous anaphylaxis (PCA) and active anaphylactic bronchoconstriction in rats were inhibited in a dose dependent manner by treatment with 7-acetyl-5-oxo-5H-[1]benzopyranol[2,3-b] pyridine (Y-9000) and disodium cromoglycate (DSCG) given intraperitoneally. The inhibitory activity of Y-9000 was to the same extent as that seen with DSCG. The IgE mediated reactions were also inhibited by oral treatment with Y-9000 but not with DSCG. In addition, the treatment with Y-9000 resulted in inhibition of IgG mediated reaction such as anaphylactic asthma in the passively sensitized guinea pigs and 4 hr heterologous PCA in rats. However, DSCG failed to prevent these reactions. Y-9000 also inhibited the active systemic anaphylaxis of the mouse and non-immunological reactions in rats such as histamine release after an intraperitoneal injection of dextran, anaphylactoid reaction and paw edema induced by the dextran, egg white or carrageenin. This agent had a stimulating effect on the adrenals, and showed glucocorticoid like activity, but bronchodilator and antagonistic activities on chemical mediators were nil. These results suggest that the anti-allergic activities of Y-9000 are elicited by inhibiting the release of allergic mediators in a manner similar to DSCG, and are partially mediated by stressor activity.     

Antiallergic activity of hesperidin is activated by intestinal microflora

When hesperidin isolated from pericarpium of Citrus unshiu (family Rutaceae) was incubated with human intestinal microflora, its main metabolite was hesperetin, which was a main metabolite in urine of orally hesperidin-administered rats. The antiallergic activity of hesperidin and its metabolite hesperetin were investigated. Hesperidin did not inhibit the histamine release from RBL-2H3 cells induced by IgE. However, its metabolite hesperetin potently inhibited the histamine release from RBL-2H3 cells induced by IgE and the PCA reaction. The inhibitory activity of hesperetin was found to be comparable with azelastine, a commercially available antiallergic drug, and to potently inhibit prostaglandin E2 production in lipopolysaccharide-stimulated RAW 264.7 cells. Hesperetin weakly inhibits cyclooxygenase 2 enzyme activities. These results suggest that hesperidin may be a prodrug, which is metabolized to hesperetin by intestinal bacteria.     

Antiallergic and anti-inflammatory properties of the ethanolic extract from Gleditsia sinensis

This study was carried out to determine the effects of the 70% ethanolic extract from the anomalous fruits of Gleditsia sinensis LAM. (AFGS) on experimental allergic reactions and inflammation. AFGS (200, 500, 1000 mg/kg, p.o.) dose-dependently inhibited the systemic anaphylactic shock induced by compound 48/80 in mice and cutaneous reactions induced by histamine or serotonin in rats. At doses of 500 and 1000 mg/kg, AFGS showed a clear inhibition on homologous passive cutaneous anaphylaxis in rats. In vitro, AFGS significantly reduced histamine release from rat peritoneal mast cells triggered by compound 48/80 at concentrations of 20 and 50 micro/ml. Moreover, AFGS (500, 1000 mg/kg, p.o.) showed a significant inhibition on the hind paw edema in rats and ear swelling in mice caused by carrageenin and croton oil, respectively. It also clearly inhibited the vascular permeability induced by acetic acid in mice at a dose of 1000 mg/kg. These findings demonstrate that the ethanolic extract from the anomalous fruits of Gleditsia sinensis possesses antiallergic and anti-inflammatory activities, which may be mediated by reducing the release of mediators such as histamine from mast cells and weakening the inflammatory action of these mediators.     

Physiological function mediated by histamine synthesis

Histamine is involved in a variety of physiologic responses, such as inflammation, type I allergy, gastric acid secretion, and neurotransmission. Previous studies have focused on specific receptors for histamine and histamine release through degranulation, and the regulation of histamine synthesis and its physiologic roles remain to be clarified. We have studied histidine decarboxylase (HDC), the rate-limiting enzyme for mammalian histamine synthesis. Immunocytochemical approaches with an anti-HDC antibody revealed that histamine synthesis occurs in two distinct compartments of mast cells, cytosol and granules, and is regulated by the posttranslational processing of HDC. We also found that histamine synthesis in mast cells is markedly induced by IgE even in the absence of antigens, which may be relevant to enhanced responses of mast cells under allergic conditions. We then developed HDC-deficient mice by gene targeting to investigate the physiologic roles of histamine. We not only confirmed that histamine is essential for type I allergy and stimulates gastric acid secretion, but also found that histamine may regulate the proliferation and differentiation of mast cells. Furthermore, in HDC-deficient mice histamine produced by infiltrated neutrophils can suppress the production of antitumoral cytokines, such as interferon-gamma and tumor necrosis factor-alpha through H2 receptors in the tumor tissues. In this review, we describe recent topics in histamine research, including our results focusing on histamine synthesis and its physiologic roles.