Mast Cell-mediated Allergic Inflammation Research Articles

Aspalathin, a Primary Rooibos Flavonoid, Alleviates Mast Cell-Mediated Allergic Inflammation by the Inhibition of FcεRI Signaling Pathway.

Mast cells are primary cells initiating allergic inflammation by the release of various allergic mediators, such as histamine and pro-inflammatory cytokines. Aspalathin (ASP) is the predominant flavonoid found exclusively in rooibos, an herb that has been traditionally used in allergy relief therapy. In the present study, we investigated the beneficial effects of ASP on mast cell-mediated allergic inflammation. For in vivo study, two well-known mast cell-mediated local and systemic allergic inflammation mouse models were used: passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis mouse models (ASA). Oral administration of ASP dose-dependently suppressed immunoglobulin (Ig)E-mediated PCA responses evidenced by Evans blue extravasation, ear thickening, and mast cell degranulation. ASP also significantly mitigated ovalbumin-induced ASA responses, including hypothermia, histamine secretion, and the production of IgE and interleukin-4. Notably, ASP was more effective in suppressing allergic inflammation than nothofagin, another prominent flavonoid known as an anti-allergic component of rooibos. The regulatory mechanism of mast cell activation by ASP was clarified using mast cell line and primary cultured mast cells (RBL-2H3 and mouse bone marrow-derived mast cells). ASP reduced IgE-stimulated mast cells degranulation and intracellular calcium influx by the inhibition of FcεRI signaling pathway (Lyn, Fyn, and Syk). Moreover, ASP reduced pro-inflammatory cytokine expressions by inhibiting two major transcription factors, nuclear factor of activated T cells and nuclear factor-κB. Collectively, we proposed that ASP could be a potential therapeutic candidate for the treatment of mast cell-mediated allergic inflammatory diseases.

Hispidulin Alleviates Mast Cell-Mediated Allergic Airway Inflammation through FcεR1 and Nrf2/HO-1 Signaling Pathway.

Allergic asthma is a type 2 immune-response-mediated chronic respiratory disease. Mast cell activation influences the pathogenesis and exacerbation of allergic asthma. Therefore, the development of mast cell-targeting pharmacotherapy is important for managing allergic airway inflammation. We investigated the efficacy of hispidulin (HPD), natural flavone, in a mast-cell-mediated ovalbumin (OVA)-induced allergic airway inflammation model. HPD alleviated symptoms of allergic asthma and decreased the levels of immunoglobulin (Ig) E, type 2 inflammation, immune cell infiltration, and mast cell activation in the lung. Furthermore, in vivo analysis confirmed the efficacy of HPD through the evaluation of IgE-mediated allergic responses in a mast cell line. HPD treatment inhibited mast cell degranulation through inhibition of the FcεR1 signaling pathway and suppressed the expression of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-13) through suppression of the NF-κB signaling pathway. The antioxidant effects of HPD in activated mast cells were identified through modulation of antioxidant enzymes and the Nrf2/HO-1 signaling pathway. In conclusion, HPD may be a potential therapeutic candidate for allergic airway inflammation of asthma and acts by suppressing mast cell activation and oxidative stress.

Therapeutic potential of ginseng leaf extract in inhibiting mast cell-mediated allergic inflammation and atopic dermatitis-like skin inflammation in DNCB-treated mice.

Ginseng leaves are known to contain high concentrations of bioactive compounds, such as ginsenosides, and have potential as a treatment for various conditions, including fungal infections, cancer, obesity, oxidative stress, and age-related diseases. This study assessed the impact of ginseng leaf extract (GLE) on mast cell-mediated allergic inflammation and atopic dermatitis (AD) in DNCB-treated mice. GLE reduced skin thickness and lymph node nodules and suppressed the expression and secretion of histamine and pro-inflammatory cytokines. It also significantly lowered the production of inflammatory response mediators including ROS, leukotriene C4 (LTC4), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). GLE inhibited the phosphorylation of MAPKs (ERK, P38, JNK) and the activation of NF-κB, which are both linked to inflammatory cytokine expression. We demonstrated that GLE's inhibitory effect on mast cell-mediated allergic inflammation is due to the blockade of the NF-κB and inflammasome pathways. Our findings suggest that GLE can be an effective therapeutic agent for mast-cell mediated and allergic inflammatory conditions.

Secreted phosphoprotein 1 regulates natural compound 3’,4’,5,7-tetrahydroxyflavone to inhibit mast cell-mediated allergic inflammation

BackgroundMast cells (MCs) are important effector cells in anaphylaxis and anaphylactic disease. 3’,4’,5,7-tetrahydroxyflavone (THF) presents in many medicinal plants and exerts a variety of pharmacological effects. In this study, we evaluated the effect of THF on C48/80-induced anaphylaxis and the mechanisms underlying its effects, including the role of secreted phosphoprotein 1 (SPP1), which has not been reported to IgE-independent MC activation.ResultsTHF inhibited C48/80-induced Ca2+ flow and degranulation via the PLCγ/PKC/IP3 pathway in vitro. RNA-seq showed that THF inhibited the expression of SPP1 and downstream molecules. SPP1 is involved in pseudo-anaphylaxis reactions. Silencing SPP1 affects the phosphorylation of AKT and P38. THF suppressed C48/80-induced paw edema, hypothermia and serum histamine, and chemokines release in vivo.ConclusionsOur results validated SPP1 is involved in IgE-independent MC activation anaphylactoid reactions. THF inhibited C48/80-mediated anaphylactoid reactions both in vivo and in vitro, suppressed calcium mobilization and inhibited SPP1-related pathways.

Amber Extract Suppressed Mast Cell-Mediated Allergic Inflammation via the Regulation of Allergic Mediators—An In Vitro Study

The various clinical approaches for treating allergy-related diseases have shown modest progress in low side effects and improved clinical outcomes. Therefore, finding alternative anti-allergic agents is crucial. The present study explored the anti-allergic effects of amber extract (fossilized tree resin) in RBL-2H3 mast cells stimulated with different allergens. In order to support the information on the inflammatory effect of the amber extract, NO production analysis on RAW 264.7 cells was conducted. β-Hexosaminidase release, an indicator of the efficacy of the amber extract in preventing mast cell activation and degranulation, reactive oxygen species (ROS) generation, and the effect of the amber extract on key cytokines production on RBL-2H3 cells, was evaluated. The results demonstrated that amber extract at concentrations up to 50 μg/mL had no cytotoxic effect on RAW 264.7 and RBL-2H3 cells. Amber extract inhibited NO production in RAW 264.7 cells. Treatment with amber extract significantly suppressed the release of β-hexosaminidase, especially at 50 μg/mL. Furthermore, amber extract suppressed the significantly increased ROS levels induced by allergen stimulation and allergy-associated cytokines. The results also suggested that amber extract exerts anti-allergic inflammatory effects by inhibiting the MAPK and NF-κB signaling pathways, resulting in decreased cytokines production. Thus, the amber extract is a promising anti-allergic agent.

Inhibition effect of PPAR-γ signaling on mast cell-mediated allergic inflammation through down-regulation of PAK1/ NF-κB activation

As a ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a crucial role in allergic inflammation. Recently, the nuclear factor kappa B (NF-κB) pathway and PAK1 have been indicated to be associated with allergic diseases. However, the effect of PPAR-γ on NF-κB and PAK1 production in food allergies is not known. This study aims to 1) systematically validate that the activation of PPAR-γ attenuates allergic reactions and 2) elucidate the mechanism by which PPAR-γ regulates mast cell degranulation. Brown Norway rats were separated into control, ovalbumin, ovalbumin + rosiglitazone, and ovalbumin + GW9662 groups. In vivo experiments demonstrated that rosiglitazone administration markedly inhibited the clinical symptoms and the serum levels of immunoglobulins E and G1. In addition, cytokine release was regulated by activated PPAR-γ and characterized by increased levels of IFN-γ and decreased levels of IL-4, IL-5, and TNF-α. Our data showed that activated PPAR-γ has the potential to alleviate food allergies by enhancing intestinal mucosal integrity and tight junctions. Moreover, we found that PPAR-γ activation inhibited mast cell degranulation both in vivo and in vitro. Our in vitro findings also showed that the activated PPAR-γ signal could inhibit PAK1 phosphorylation and the expression of p65. Furthermore, the interaction between p65 and p-PAK1 during ovalbumin treatment was attenuated after PPAR-γ activation. Collectively, these results demonstrate that PPAR-γ is an important regulator of mast cell degranulation and the Th2-type response, which sheds new light on the importance of PPAR-γ in food allergies.

Oleanolic Acid Alleviates Atopic Dermatitis-like Responses In Vivo and In Vitro.

Oleanolic acid (OA) is a pentacyclic triterpenoid, abundantly found in plants of the Oleaceae family, and is well known for its beneficial pharmacological activities. Previously, we reported the inhibitory effect of OA on mast cell-mediated allergic inflammation. In this study, we investigated the effects of OA on atopic dermatitis (AD)-like skin lesions and its underlying mechanism of action. We evaluated the inhibitory effect of OA on AD-like responses and the possible mechanisms using a 1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced AD animal model and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes. We found that OA has anti-atopic effects, including histological alterations, on DNCB-induced AD-like lesions in mice. Moreover, it suppressed the expression of Th2 type cytokines and chemokines in the AD mouse model and TNF-α/IFN-γ-induced HaCaT keratinocytes by blocking the activation of serine-threonine kinase Akt, nuclear factor-κB, and the signal transducer and activator of transcription 1. The results demonstrate that OA inhibits AD-like symptoms and regulates the inflammatory mediators; therefore, it may be used as an effective and attractive therapeutic agent for allergic disorders, such as AD. Moreover, the findings of this study provide novel insights into the potential pharmacological targets of OA for treating AD.

Inhibition Effect of PPAR-γ Signaling on Mast Cell-Mediated Allergic Inflammation Through Down-Regulation of PAK1/ NF-κB Activation

Inhibition Effect of PPAR-γ Signaling on Mast Cell-Mediated Allergic Inflammation Through Down-Regulation of PAK1/ NF-κB Activation

Imperatorin ameliorates mast cell-mediated allergic airway inflammation by inhibiting MRGPRX2 and CamKII/ERK signaling pathway

BackgroundAllergic asthma is a common inflammatory lung disease associated with complex pathogenesis. Mast cell (MC) is one of the key drivers of allergic asthma, Mas-related G protein-coupled receptor X2 (MRGPRX2) on the MC could mediate MC activation and trigger a pseudo-allergic reaction. Imperatorin (IMP), the main active compound of Radix Angelicae Dahuricae, has been reported to exert various pharmacological effects. In this study, we focused on the therapeutical mechanism of IMP on MRGPRX2-induced pseudo-allergy and allergic asthma. MethodsWe examined the effect of IMP on MRGPRX2 related mast cell activation in mouse peritoneal MC (MPMC), Human Laboratory of Allergic Disease 2 MCs (LAD2 cells) and Mrgprx2-expressing HEK293 cells. Molecular docking and Surface plasmon resonance (SPR) were taken to reveal the binding character between IMP and MRPGRX2. MRGPRX2 downstream proteins were also detected by western blotting. IgE-independent responses was evaluated by using passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) models. The therapeutic effect of IMP on asthma was evaluated by a lung inflammation mouse model which was induced by ovalbumin (OVA). ResultsIMP was found to reduce substance P (SP) induced calcium flux and suppressed degranulation of MC. SP can promote the phosphorylation of ERK and CamKII, which regulates the synthesis of inflammatory factors such as MIP-2 and TNF-α in MC. In vivo assays revealed that IMP can mitigate SP-induced mouse PCA and ASA. IMP could also mitigate lung inflammation in an OVA induced mice model by inhibiting MC activation in the lung tissue. Furthermore, IMP binds well to MRGPRX2 protein. The binding constant (KD) is 4.48 ± 0.49 × 10−7 M. The data suggeste that IMP is a novel inhibitor of MRGPRX2 to treat allergic asthma.

Extract of Boehmeria nivea Suppresses Mast Cell-Mediated Allergic Inflammation by Inhibiting Mitogen-Activated Protein Kinase and Nuclear Factor-κB.

Mast cells are effector cells that initiate allergic inflammatory immune responses by inducing inflammatory mediators. Boehmeria nivea (Linn.) Gaudich is a natural herb in the nettle family Urticaceae that possesses numerous pharmacological properties. Despite the various pharmacological benefits of Boehmeria nivea, its effects on allergic inflammation have not yet been determined. Here, we investigated the effect of the ethanol extract of Boehmeria nivea (BNE) on degranulation rat basophilic leukemia (RBL)-2H3 mast cells stimulated with anti-dinitrophenyl (anti-DNP) and bovine serum albumin (BSA) during immunoglobulin E (IgE)-mediated allergic immune response. The results showed inhibition of the release of β-hexosaminidase and histamine from the cells. BNE suppressed pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, and IL-6) and reduced T helper (Th)2 cytokine IL-4 expression and/or secretion correlated with the downregulation of p38, extracellular signal-regulated kinases (ERK) mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling pathways in treated RBL-2H3 mast cells. In passive cutaneous anaphylaxis, treatment with BNE during IgE-mediated local allergic reaction triggered a reduction in mouse ear pigmentation and thickness. Taken together, these results indicated that BNE suppressed mast cell-mediated inflammation, suggesting that BNE might be a candidate for the treatment of various allergic disorders.

AGK2 ameliorates mast cell-mediated allergic airway inflammation and fibrosis by inhibiting FcεRI/TGF-β signaling pathway

Asthma is characterized by airway hyperresponsiveness and allergic inflammation, detrimentally affecting the patients’ quality of life. The development of new drugs for the treatment of asthma is warranted to alleviate these issues. Recent studies have demonstrated that sirtuin2 (SIRT2) aggravates asthmatic inflammation by up-regulation of T-helper type 2 responses and macrophage polarization. However, effects of SIRT2 on mast cell activation remain obscure. In this study, we investigated the effects of AGK2, an inhibitor for SIRT2, on mast cell-mediated allergic airway inflammation. Pre-treatment with AGK2 inhibited degranulation of mast cells by suppressing the FcεRI signaling pathway and intracellular calcium influx. The expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-5, IL-6, and IL-8, was inhibited via regulation of transcription factors such as NF-κB and NRF2. These effects of AGK2 were verified in passive cutaneous anaphylaxis and acute lung injury animal models. AGK2 attenuated Evans blue pigmentation by inhibiting mast cell activation and lung barrier dysfunction by inhibiting inflammatory responses in these animal models. In the ovalbumin (OVA)-induced allergic airway inflammation murine model, AGK2 alleviated allergic asthma symptoms such as lung histological changes (immune cell and mast cell infiltration, collagen deposition, and α-smooth muscle actin expression) and serum immunoglobulins (Ig) levels (IgE, OVA-specific IgE, IgG1, and IgG2a). Moreover, AGK2 reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-4, IL-5, and IL-6) and inflammatory mediators (myeloperoxidase, eosinophil peroxidase, and tumor growth factor-α) in the bronchoalveolar lavage fluid and lung tissues. In addition, the anti-fibrotic effects of AGK2 were verified using lung epithelial cells and TGF-β/Smad reporter stable cells. In conclusion, our findings suggest that SIRT2 plays a role in mast cell-mediated airway inflammatory disease. Therefore, AGK2 is a good potential candidate for treating allergic asthma and lung inflammation.

SG-SP1 suppresses mast cell-mediated allergic inflammation via inhibition of FcɛRI signaling

Abstract As the number of allergic disease cases increases, studies to identify new treatments take on new urgency. In previous study, gallic acid (GA), a part of EGCG, a major component of green tea, has shown anti-allergic inflammatory effect. However, GA has low metabolic stability and structure-activity relationship. Therefore, we designed SG-SP1 based on GA. We aimed to assess the effects of SG-SP1 on mast cell-mediated allergic inflammation using various animal and in vitro models. For in vitro experiments, IgE-mediated various mast cells (RBL-2H3 and primary cultured peritoneal and bone marrow-derived mast cells) were used to determine the role of SG-SP1 (0.1–1 nM). Immunoglobulin (Ig) E-induced passive cutaneous anaphylaxis and Ovalbumin-induced systemic anaphylaxis are standard animal models for immediate-type hypersensitivity. For in vitro, SG-SP1 reduced degranulation of mast cells by down-regulating intracellular calcium levels in a concentration-dependent manner. In addition, SG-SP1 decreased expression and secretion of inflammatory cytokines in activated mast cells. This suppressive effect was associated to inhibition of the phosphorylation of Lyn, Syk and Akt, and the nuclear translocation of nuclear factor-κB. Due to the strong inhibitory effect of SG-SP1 on Lyn, the known upstream signaling of FcɛRI-dependent pathway, we confirmed the direct binding of SG-SP1 to FcɛRI, a high affinity IgE receptor by surface plasmon resonance experiment. We determined that SG-SP1 directly interacts with FcɛRI and propose SG-SP1 as a therapeutic candidate for mast cell-mediated allergic inflammatory disorders via inhibition of FcɛRI signaling.

SG-SP1 Suppresses Mast Cell-Mediated Allergic Inflammation via Inhibition of FcεRI Signaling

Background: As the number of allergic disease increases, studies to identify new treatments take on new urgency. Epigallocatechin gallate (EGCG), a major component of green tea, has been shown to possess a wide range of pharmacological properties, including anti-inflammation and anti-viral infection. In previous study, gallic acid (GA), a part of EGCG, has shown anti-allergic inflammatory effect. To improve on preliminary evidence that GA has allergy mitigating effect, we designed SG-SP1 based on GA, and aimed to assess the effects of SG-SP1 on mast cell-mediated allergic inflammation using various animal and in vitro models.Methods: For in vitro experiments, various types of IgE-stimulated mast cells (RBL-2H3: mast cell-like basophilic leukemia cells, and primary cultured peritoneal and bone marrow-derived mast cells) were used to determine the role of SG-SP1 (0.1–1 nM). Immunoglobulin (Ig) E-induced passive cutaneous anaphylaxis and ovalbumin-induced systemic anaphylaxis, standard animal models for immediate-type hypersensitivity were also used.Results: For in vitro, SG-SP1 reduced degranulation of mast cells by down-regulating intracellular calcium levels in a concentration-dependent manner. SG-SP1 decreased expression and secretion of inflammatory cytokines in activated mast cells. This suppressive effect was associated with inhibition of the phosphorylation of Lyn, Syk and Akt, and the nuclear translocation of nuclear factor-κB. Due to the strong inhibitory effect of SG-SP1 on Lyn, the known upstream signaling to FcεRI-dependent pathway, we confirmed the direct binding of SG-SP1 to FcεRI, a high affinity IgE receptor by surface plasmon resonance experiment. Oral administration of SG-SP1 hindered allergic symptoms of both anaphylaxis models evidenced by reduction of hypothermia, serum IgE, ear thickness, and tissue pigmentation. This inhibition was mediated by the reductions in serum histamine and interleukin-4.Conclusions: We determined that SG-SP1 directly interacts with FcεRI and propose SG-SP1 as a therapeutic candidate for mast cell-mediated allergic inflammatory disorders via inhibition of FcεRI signaling.

Inhibitory effects of orientin in mast cell-mediated allergic inflammation.

Mast cells are immune effector cells mediating allergic inflammation by the secretion of inflammatory mediators such as histamine and pro-inflammatory cytokines. Orientin is a naturally occurring bioactive flavonoid that possesses diverse biological properties, including anti-inflammation, anti-oxidative, anti-tumor, and cardio protection. The objective of this study was to rule out the effectiveness of orientin in mast cell-mediated allergic inflammation. In this study, in vitro effects of orientin were evaluated in RBL-2H3, mouse bone marrow-derived mast cells, rat peritoneal mast cells, and in vivo effects were evaluated by inducing passive cutaneous anaphylaxis (PCA) in Imprinting Control Region (ICR) mice. Findings show that orientin suppressed the immunoglobulin E (IgE)-mediated mast cell degranulation by reducing intracellular calcium level in a concentration-dependent manner. Orientin suppressed the secretion of pro-inflammatory cytokines in mast cells. This inhibitory effects of orientin was through inhibition of FcεRI-mediated signaling proteins. In addition, oral administration of orientin suppressed the IgE-mediated PCA reactions in a dose-dependent manner, which was evidenced by reduced Evan's blue pigmentation and ear swelling. Based on these findings, we suggest that orientin might have potential to alleviate allergic reaction and mast cell-mediated allergic disease.

Prunus serrulata var. spontanea inhibits mast cell activation and mast cell-mediated anaphylaxis.

A promising approach to treat a variety of diseases are considered as complementary and alternative herbal medicines. Prunus serrulata var. spontanea L. (Rosaceae) is used as herbal medicine to treat allergic diseases according to the Donguibogam, a tradition medical book of the Joseon Dynasty in Korea. We prepared the aqueous extract of the bark of P. serrulata (AEBPS) and aimed to investigate the effects in mouse anaphylaxis models and various types of mast cells, including RBL-2H3, primary cultured peritoneal and bone marrow-derived mast cells. We used ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and immunoglobulin (Ig) E-mediated passive cutaneous anaphylaxis (PCA) models, in vivo. The control drug dexamethasone (10mg/kg) was used to compare the effectiveness of AEBPS (1-100mg/kg). In vitro, IgE-stimulated mast cells were used to confirm the role of AEBPS (1-100μg/mL). For statistical analyses, p values less than 0.05 were considered to be significant. In ASA model, oral administration of AEBPS suppressed the hypothermia and increased level of serum histamine in a dose-dependent manner. AEBPS attenuated the serum IgE, OVA-specific IgE, and interleukin (IL)-4. Oral administration of AEBPS also blocked mast cell-dependent PCA. AEBPS suppressed degranulation of mast cells by reducing intracellular calcium level in mast cells. AEBPS inhibited tumor necrosis factor-α and IL-4 expression and secretion in a concentration-dependent manner through the reduction of nuclear factor-κB. On the basis of these findings, AEBPS could serve as a potential therapeutic target for the management of mast cell-mediated allergic inflammation and as a regulator of mast cell activation.

Gomisin M2 Inhibits Mast Cell-Mediated Allergic Inflammation via Attenuation of FcεRI-Mediated Lyn and Fyn Activation and Intracellular Calcium Levels.

Mast cells are effector cells that induce allergic inflammation by secreting inflammatory mediators. Gomisin M2 (G.M2) is a lignan isolated from Schisandra chinensis (Turcz). Baill. exhibiting anti-cancer activities. We aimed to investigate the anti-allergic effects and the underlying mechanism of G.M2 in mast cell–mediated allergic inflammation. For the in vitro study, we used mouse bone marrow–derived mast cells, RBL-2H3, and rat peritoneal mast cells. G.M2 inhibited mast cell degranulation upon immunoglobulin E (IgE) stimulation by suppressing the intracellular calcium. In addition, G.M2 inhibited the secretion of pro-inflammatory cytokines. These inhibitory effects were dependent on the suppression of FcεRI-mediated activation of signaling molecules. To confirm the anti-allergic effects of G.M2 in vivo, IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were utilized. Oral administration of G.M2 suppressed the PCA reactions in a dose-dependent manner. In addition, G.M2 reduced the ASA reactions, including hypothermia, histamine, interleukin-4, and IgE production. In conclusion, G.M2 exhibits anti-allergic effects through suppression of the Lyn and Fyn pathways in mast cells. According to these findings, we suggest that G.M2 has potential as a therapeutic agent for the treatment of allergic inflammatory diseases via suppression of mast cell activation.

Hispidulin Inhibits Mast Cell-Mediated Allergic Inflammation through Down-Regulation of Histamine Release and Inflammatory Cytokines.

Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a natural compound derived from traditional Chinese medicinal herbs, and it is known to have an anti-inflammatory effect. Here, we investigated the effect of hispidulin on the immunoglobulin E (IgE)-mediated allergic responses in rat basophilic leukemia (RBL)-2H3 mast cells. When RBL-2H3 cells were sensitized with anti-dinitrophenyl (anti-DNP) IgE and subsequently stimulated with DNP-human serum albumin (HSA), histamine and β-hexosaminidase were released from the cells by degranulation of activated mast cells. However, pretreatment with hispidulin before the stimulation of DNP-HSA markedly attenuated release of both in anti-DNP IgE-sensitized cells. Furthermore, we investigated whether hispidulin inhibits anti-DNP IgE and DNP-HSA-induced passive cutaneous anaphylaxis (PCA), as an animal model for Type I allergies. Hispidulin markedly decreased the PCA reaction and allergic edema of ears in mice. In addition, activated RBL-2H3 cells induced the expression of inflammatory cytokines (tumor necrosis factor-α and interleukin-4), which are critical for the pathogenesis of allergic disease, through the activation of c-Jun N-terminal kinase (JNK). Inhibition of JNK activation by hispidulin treatment reduced the induction of cytokine expression in the activated mast cells. Our results indicate that hispidulin might be a possible therapeutic candidate for allergic inflammatory diseases through the suppression of degranulation and inflammatory cytokines expression.

Protective effect of linoleic acid against inflammatory reactions by mast cell via caspase-1 cascade pathways.

Blockade of caspase-1 was reported to be a new target for allergic inflammation treatment. Here, we present the effect of linoleic acid (LA), a constituent of Allium hookeri (AH), to alleviate mast cell-mediated allergic inflammation. Pretreatment of LA and AH significantly reduced caspase-1 activation without displaying host cell cytotoxicity in activated human mast cells. IC50 value of LA on caspase-1 activity is 0.014μM. LA and AH pretreatment effectively regulated increased levels of interleukin (IL)-1β, IL-6, IL-8, thymic stromal lymphopoietin, and tumor necrosis factor on activated human mast cells. Moreover, LA and AH were effective against activations of nuclear factor-κB and mitogen-activated protein kinases in human mast cells. In summary, LA and AH alleviate allergic inflammatory reactions via blocking caspase-1 cascade signaling pathway. These results provide evidence for the anti-allergic inflammatory properties of LA and AH and corroborate its potential use for the treatment and prevention of allergic diseases. PRACTICAL APPLICATIONS: Allium hookeri (AH) is used as traditional food to treat various diseases and contains an essential fatty acid, linoleic acid (LA). LA and AH alleviate mast cell-mediated allergic inflammatory reactions via inhibiting inflammatory mediators. These results provide evidence for the anti-allergic inflammatory properties of LA and AH and corroborate its potential use for the treatment and prevention of allergic diseases.

Avenanthramide C from germinated oats exhibits anti-allergic inflammatory effects in mast cells

Mast cells play a crucial role in allergic diseases via the release of inflammatory mediators, particularly histamine and pro-inflammatory cytokines. Avenanthramide (Avn) C, a polyphenol found mainly in oats, is known to exhibit various biological properties. In this study, we aimed to evaluate the effectiveness of Avn C from germinated oats against mast cell-mediated allergic inflammation. For the in vitro study, RBL-2H3, mouse bone marrow-derived mast cells and rat peritoneal mast cells were used. Avn C (1–100 nM) inhibited the immunoglobulin (Ig)E-stimulated mast cells degranulation by suppressing phosphorylation of phosphoinositide 3-kinase and phospholipase Cγ1 and decreasing intracellular calcium levels. It inhibited IgE-stimulated secretion of inflammatory cytokines via suppression of FcεRI-mediated signaling proteins Lyn, Syk, Akt, and nuclear factor-κB. To verify the effects of Avn C in vivo, ovalbumin-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. Oral administration of Avn C dose-dependently attenuated the ASA reactions, as evidenced by the inhibition of hypothermia and reduction of elevated serum histamine, IgE, and interleukin-4 levels. Avn C also inhibited the PCA reactions, such as ear swelling and plasma extravasation. Our results suggested that Avn C from germinated oats might be a possible therapeutic candidate for mast cell-mediated allergic inflammation.

Elaeocarpusin Inhibits Mast Cell-Mediated Allergic Inflammation.

Mast cells are major effector cells for allergic responses that act by releasing inflammatory mediators, such as histamine and pro-inflammatory cytokines. Accordingly, different strategies have been pursued to develop anti-allergic and anti-inflammatory candidates by regulating the function of mast cells. The purpose of this study was to determine the effectiveness of elaeocarpusin (EL) on mast cell-mediated allergic inflammation. We isolated EL from Elaeocarpus sylvestris L. (Elaeocarpaceae), which is known to possess anti-inflammatory properties. For this study, various sources of mast cells and mouse anaphylaxis models were used. EL suppressed the induction of markers for mast cell degranulation, such as histamine and β-hexosaminidase, by reducing intracellular calcium levels. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and IL-4, was significantly decreased in activated mast cells by EL. This inhibitory effect was related to inhibition of the phosphorylation of Fyn, Lyn, Syk, and Akt, and the nuclear translocation of nuclear factor-κB. To confirm the effect of EL in vivo, immunoglobulin E-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were induced. EL reduced the PCA reaction in a dose dependent manner. In addition, EL attenuated ASA reactions such as hypothemia, histamine release, and IgE production. Our results suggest that EL is a potential therapeutic candidate for allergic inflammatory diseases that acts via the inhibition of mast cell degranulation and expression of proinflammatory cytokines.