Mast Cell-mediated Allergic Reactions Research Articles

Moringa oleifera Leaves Protein Enhances Intestinal Permeability by Activating TLR4 Upstream Signaling and Disrupting Tight Junctions.

Changes in intestinal mucosal barrier permeability lead to antigen sensitization and mast cell-mediated allergic reactions, which are considered to play important roles in the occurrence and development of food allergies. It has been suggested that protein causes increased intestinal permeability via mast cell degranulation, and we investigated the effect of camellia Moringa oleifera leaves protein on intestinal permeability and explored its role in the development of food allergies. The current study investigated the effect of M. oleifera leaves protein on intestinal permeability through assessments of transepithelial electrical resistance (TEER) and transmembrane transport of FITC-dextran by Caco-2 cells. The expression levels of Toll-like receptor 4 (TLR4), IL-8, Occludin, Claudin-1, and perimembrane protein family (ZO-1) were detected by real-time PCR and Western blotting. The effect of M. oleifera leaves protein on intestinal permeability was verified in mice in vivo. The serum fluorescence intensity was measured using the FITC-dextran tracer method, and the expression of tight junction proteins was detected using Western blotting. The results showed that M. oleifera leaves protein widened the gaps between Caco-2 cells, reduced transmembrane resistance, and increased permeability. This protein also reduced the mRNA and protein levels of Occludin, Claudin-1, and ZO-1. Animal experiments showed that intestinal permeability was increased, and that the expression of the tight junction proteins Occludin and Claudin-1 were downregulated in mice. This study shows that M. oleifera leaves protein has components that increase intestinal permeability, decrease tight junction protein expression, promote transmembrane transport in Caco-2 cells, and increase intestinal permeability in experimental animals. The finding that M. oleifera leaves active protein increases intestinal permeability suggests that this protein may be valuable for the prevention, diagnosis, and treatment of M. oleifera leaves allergy.

Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN.

Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory properties of thalidomide have been reported, little is known about its influence on the mast cell-mediated allergic reaction. In the present study, we aimed to evaluate the anti-allergic activity of thalidomide and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and passive cutaneous anaphylaxis (PCA) mouse models. Thalidomide markedly decreased the degranulation and release of lipid mediators and cytokines in IgE/Ag-stimulated BMMCs, with concurrent inhibition of FcεRI-mediated positive signaling pathways including Syk and activation of negative signaling pathways including AMP-activated protein kinase (AMPK) and SH2 tyrosine phosphatase-1 (SHP-1). The knockdown of AMPK or SHP-1 with specific siRNA diminished the inhibitory effects of thalidomide on BMMC activation. By contrast, the knockdown of cereblon (CRBN), which is the primary target protein of thalidomide, augmented the effects of thalidomide. Thalidomide reduced the interactions of CRBN with Syk and AMPK promoted by FcεRI crosslinking, thereby relieving the suppression of AMPK signaling and suppressing Syk signaling. Furthermore, oral thalidomide treatment suppressed the PCA reaction in mice. In conclusion, thalidomide suppresses FcεRI-mediated mast cell activation by activating the AMPK and SHP-1 pathways and antagonizing the action of CRBN, indicating that it is a potential anti-allergic agent.

Oleanolic Acid Acetate Inhibits Mast Cell Activation in Ovalbumin-Induced Allergic Airway Inflammation.

Asthma is a complex, heterogeneous chronic inflammatory airway disease with multiple phenotypes. There has been a great progress in managing asthma, but there are still unmet needs for developing uncontrolled asthma treatments. The present study aimed to determine the effectiveness of oleanolic acid acetate (OAA) from Vigna angularis against allergic airway inflammation and the underlying mechanism of action with a focus on mast cells. To investigate the effect of OAA in allergic airway inflammation, we used the ovalbumin (OVA)-sensitized and challenged mice. To examine allergic airway inflammation associated with immune responses of mast cell activation in vitro, various types of mast cells were used. Systemic and cutaneous anaphylaxis models were used for mast cell-mediated hyper-responsiveness in vivo. OAA reduced OVA-induced airway inflammatory responses such as bronchospasm, increase of immune cell infiltration and serum immunoglobulin E and G1 levels. Especially, OAA decreased the mast cell infiltration, and β-hexosaminidase release as a mast cell activation marker in the bronchoalveolar lavage fluid. OAA inhibited mast cell degranulation in mast cell line (RBL-2H3) and primary cells (rat peritoneal mast cell and mouse bone marrow-derived mast cell). Mechanistically, OAA suppressed intracellular signaling pathways including the phosphorylation of phospholipase Cγ and nuclear factor-κB, resulting from the suppression of intracellular calcium influx and pro-inflammatory cytokine expression. Further, oral administration of OAA attenuated mast cell-mediated systemic and cutaneous anaphylaxis. Our study showed that OAA can inhibit mast cell-mediated allergic reaction. Consequently, the application of OAA to mast cells for the allergic airway inflammation facilitate a new direction of treating allergic asthma.

RANKL down-regulates the mast cell proliferation through inducing senescence.

An increase in the number of mast cells could contribute to inflammatory diseases and pathologic conditions. A receptor activator of NF-κB ligand (RANKL)/RANK system is one of the key signaling pathways accelerating mast cell-mediated allergic inflammatory reactions. However, the biological functions of RANKL in mast cell proliferation remains to be clarified. The aim of the present study is to clarify the role of RANKL in mast cell proliferation. Surprisingly, RANKL remarkably reduced the proliferation of human mast cell line, HMC-1 cells through the inhibition of murine double minute 2 (MDM2) and Ki-67 mRNA expressions in a dose-dependent manner. RANKL significantly reduced cell viability, whereas it increased cellular senescence via increasing levels of p53, phosphorylated(p)-p53, p21, and p16 and decreasing levels of retinoblastoma protein (pRb) and p-pRb in HMC-1 cells. Even in rat peritoneal mast cells, RANKL induced cellular senescence by increasing filamentous-actin polymerization. In addition, RANKL remarkably reduced thymic stromal lymphopoietin (TSLP)-induced mast cell proliferation via the downregulation of MDM2 and Ki-67. RANKL decreased levels of p-signal transducer and activator of transcription 6 in TSLP-stimulated HMC-1 cells. The mast cell growth factor, interleukin-13 was remarkably down-regulated by treatment with RANKL in TSLP-stimulated HMC-1 cells. Furthermore, RANKL increased the number of senescence-associated β-galactosidase-stained cells and protein levels of p53, p-p53, and p21 in TSLP-stimulated HMC-1 cells. These data suggest that RANKL down-regulates mast cell proliferation by inducing senescence.

Front Cover: Resveratrol Attenuates Mast Cell Mediated Allergic Reactions: Potential for Use as a Nutraceutical in Allergic Diseases?

Mol. Nutr. Food Res. 2022, 66, 202200170 DOI: 10.1002/mnfr.202200170 Resveratrol, a polyphenol found in red grapes, inhibits release of pre-stored and newly synthesized pro-inflammatory mediators in mast cells activated by various stimuli. Signaling pathways inhibited by resveratrol include among others MAP kinases ERK and p38 as well as transcription factors STAT3 and NF-κB. This is reported by Axel Lorentz and co-workers in article number 2200170.

Resveratrol Attenuates Mast Cell Mediated Allergic Reactions: Potential for Use as a Nutraceutical in Allergic Diseases?

Allergic diseases are one of the most common health disorders affecting about 30% of the world population. Mast cells (MCs) are key effector cells of allergic reactions by releasing proinflammatory mediators including histamine, lipid mediators, and cytokines/chemokines. Natural substances like secondary plant substances such as resveratrol (RESV), which can contribute to prevention and treatment of diseases, are becoming increasingly interesting for use as nutraceuticals. In this review, the anti-inflammatory effects of RESV on MC-mediated allergic reactions in vitro and in vivo models are summarized. The studies indicate that RESV inhibits MC degranulation, synthesis of arachidonic acid metabolites, expression of cytokines and chemokines as well as activation of signal molecules involved in proinflammatory mechanisms. Also, beneficial impacts by this polyphenol are reported in randomized controlled trials with allergic rhinitis patients. Although it cannot yet be concluded that RESV can be used successfully in allergy patients in general, there are many results that indicate a possible role for RESV for use as an anti-inflammatory nutraceutical. However, strategies to favorably influence the poor bioavailability of RESV would be helpful.

Pterostilbene Inhibits FcεRI Signaling through Activation of the LKB1/AMPK Pathway in Allergic Response.

In this study, the role and mechanism of pterostilbene (Pts) in mast cell degranulation in vitro and in vivo were investigated. The results showed that Pts inhibited mast cell-mediated local passive allergic reactions in mice. In addition, treatment with Pts reduced both histamine release and calcium influx in rat peritoneal mast cells and RBL-2H3 cells and reduced IgE-mediated mast cell activation. Furthermore, the mechanism underlying Pts inhibition of mast cell signaling was probed via studying the effects of Pts on liver kinase B1 (LKB1), including the use of the LKB1 activator metformin and siRNA knockdown of LKB1. The data showed that Pts reduced the release of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, leukotriene C4, and prostaglandin D2 in mast cells by activating the LKB1/adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Furthermore, Pts inhibited phosphorylation of FcεRI and FcεRI-mediated degranulation in RBL-2H3 cells. These effects were attenuated after LKB1 knockdown. Taken together, Pts could inhibit FcεRI signaling through activation of the LKB1/AMPK signaling pathway in IgE-mediated mast cell activation. Thus, Pts might be an effective therapeutic agent for mast cell-mediated allergic diseases.

Sulforaphane mitigates mast cell-mediated allergic inflammatory reactions in in silico simulation and in vitro models

Objectives: Sulforaphane, a major ingredient isolated from Brassica oleracea var. italica (broccoli), is known to exhibit anti-inflammatory, anti-cancer, and anti-diabetic effects. In this study, we employed an in vitro model of phorbol 12-myristate 13-acetate and a23187 (PMACI)-stimulated human mast cells (HMC-1 cells) to investigate the anti-allergic inflammatory effects and mechanisms of sulforaphane and Brassica oleracea var. italica extracts.Methods: Cytokine levels were measured by ELISA and quantitative real-time-PCR methods. Caspase-1 activity was determined by caspase-1 assay. Binding mode of sulforaphane within caspase-1 was determined by molecular docking simulation. Protein expression was determined by Western blotting.Results: Water extract of Brassica oleracea var. italica (WE) significantly reduced thymic stromal lymphopoietin (TSLP) secretion and caspase-1 activity on activated HMC-1 cells. In the molecular docking simulation and in vitro caspase-1 assays, sulforaphane regulated caspase-1 activity by docking with the identical binding site of caspase-1. Sulforaphane significantly inhibited the levels of inflammatory mediators including TSLP, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in a dose-dependent manner. Immunoblotting experiments revealed that sulforaphane and WE reduced translocation of NF-κBp65 into the nucleus and phosphorylation of IκBα in the cytosol. Furthermore, phosphorylation of mitogen-activated protein kinases (MAPK) was down-regulated by treatment with sulforaphane or WE.Conclusion: Our findings suggest that sulforaphane and WE have anti-allergic inflammatory effects by intercepting caspase-1/NF-κB/MAPKs signaling pathways.

Endogenous Annexin-A1 Negatively Regulates Mast Cell-Mediated Allergic Reactions.

Mast cell stabilizers like cromoglycate and nedocromil are mainstream treatments for ocular allergy. Biochemical studies in vitro suggest that these drugs prevent mast cell degranulation through the release of Annexin-A1 (Anx-A1) protein. However, the direct effect of Anx-A1 gene deletion on mast cell function in vitro and in vivo is yet to be fully investigated. Hence, we aim to elucidate the role of Anx-A1 in mast cell function, both in vivo and in vitro, using a transgenic mouse model where the Anx-A1 gene has been deleted. Bone marrow-derived mast cells (BMDMCs) were cultured from wild-type animals and compared throughout their development to BMDMCs obtained from mice lacking the Anx-A1 gene. The mast cell differentiation, maturity, mediator, and cytokine release were explored using multiple biochemical techniques, such as Western blots, ELISA, and flow cytometry analysis. Electron microscopy was used to identify metachromatic granules content of cells. For in vivo studies, Balb/C wild-type and Anx-A1-deficient mice were divided into the following groups: group 1, a control receiving only saline, and group 2, which had been sensitized by prior exposure to short ragweed (SRW) pollen by topical contact with the conjunctival mucosae. Allergic conjunctivitis was evaluated blind after 24 h by trained observers scoring clinical signs. Electron micrographs of BMDMCs from Anx-A1-null mice revealed more vacuoles overall and more fused vacuoles than wild-type cells, suggesting enhanced secretory activity. Congruent with these observations, BMDMCs lacking the Anx-A1 gene released significantly increased amounts of histamine both spontaneously as well as in response to Ig-E-FcεRI cross-linking compared to those from wild-type mice. Interestingly, the spontaneous release of IL-5, IL-6, IL-9, and monocyte chemoattractant protein-1 (MCP-1) were also markedly increased with a greater production observed upon IgE cross-linking. This latter finding is congruent with augmented calcium mobilization in BMDMCs lacking the Anx-A1 gene. In vivo, when compared to wild-type animals, Anx-A1-deficient mice exposed to SRW pollen displayed exacerbated signs and symptoms of allergic conjunctivitis. Taken together, these results suggest Anx-A1 is an important non-redundant regulator of mast cell reactivity and particularly in allergen mediated allergic reactions.

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.

Inhibitory effect of taxifolin on mast cell activation and mast cell-mediated allergic inflammatory response

The aim of the present study is to investigate the anti-inflammatory and anti-allergic effects of taxifolin on mast cells and mast cell-mediated allergic reaction. We assessed the effect of taxifolin on the activation of bone marrow-derived mast cells (BMMCs) and rat basophilic leukemia (RBL)-2H3 cells induced by immunoglobulin E (IgE)/antigen (Ag), and the activation of human mast cell line (HMC-1) induced by PMA plus A23187. Taxifolin inhibited degranulation, generation of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) through blocking intracellular Ca2+ mobilization, phosphorylation of phospholipase Cγ (PLCγ) and mitogen-activated protein kinases (MAPKs), translocation of cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO), and Akt/IKK/NF-κB pathway, in BMMC cells. Furthermore, taxifolin suppressed phosphorylation of Syk, but without effect on Fyn and Lyn. Taxifolin also inhibited activation of RBL-2H3 and HMC-1 cells via Akt/IKK/NF-κB and MAPKs/cPLA2 signal pathway. Treatment with taxifolin attenuated the mast cell-mediated passive cutaneous anaphylaxis (PCA) reaction. Our results suggest that taxifolin might become a potential drug candidate for the treatment of allergic and inflammatory diseases.

The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets.

Histamine and its receptors (H1R–H4R) play a crucial and significant role in the development of various allergic diseases. Mast cells are multifunctional bone marrow-derived tissue-dwelling cells that are the major producer of histamine in the body. H1R are expressed in many cells, including mast cells, and are involved in Type 1 hypersensitivity reactions. H2R are involved in Th1 lymphocyte cytokine production. H3R are mainly involved in blood–brain barrier function. H4R are highly expressed on mast cells where their stimulation exacerbates histamine and cytokine generation. Both H1R and H4R have important roles in the progression and modulation of histamine-mediated allergic diseases. Antihistamines that target H1R alone are not entirely effective in the treatment of acute pruritus, atopic dermatitis, allergic asthma, and other allergic diseases. However, antagonists that target H4R have shown promising effects in preclinical and clinical studies in the treatment of several allergic diseases. In the present review, we examine the accumulating evidence suggesting novel therapeutic approaches that explore both H1R and H4R as therapeutic targets for histamine-mediated allergic diseases.

Src-type tyrosine kinase p56lck is critical for thymic stromal lymphopoietin-induced allergic rhinitis.

Thymic stromal lymphopoietin (TSLP) is a regulator of mast cell-mediated allergic inflammatory reactions, but the manner in which TSLP contributes to allergic rhinitis (AR) remains unclear. Here, we sought to determine that TSLP plays a crucial role in AR by interacting with Src-type tyrosine kinase p56lck and STAT6 and promoting mast cells degranulation. The effects of TSLP on mast cell degranulation and AR were analysed in human mast cell line (HMC-1 cells), ovalbumin (OVA)-induced AR animal model, and human subjects. Small interfering RNA experiments were performed in HMC-1 cells and OVA-induced AR model. Immune responses were analysed by enzyme-linked immunosorbent assay, Western blotting, immunoprecipitation, and histological studies. Thymic stromal lymphopoietin levels and mast cell-derived p56lck activation were elevated in human subjects with AR, and in AR mice, exogenous TSLP accelerated TH2-allergic inflammatory reactions by up-regulating p56lck and STAT6. On the other hand, depletion of TSLP, p56lck, and STAT6 ameliorated clinical symptoms in AR mice. The selective inhibitor of p56lck, damnacanthal, inhibits AR reactions. Collectively, these observations suggest a role for TSLP/p56lck/STAT6 in AR and offer insight into potential therapeutic strategies.

Inhibitory effect of naringenin via IL-13 level regulation on thymic stromal lymphopoietin-induced inflammatory reactions.

Naringenin (NG) has various beneficial properties, such as anti-cancer and anti-inflammatory effects. Thymic stromal lymphopoietin (TSLP) induces mast cell proliferation and inflammatory reactions. The aim of this study was to investigate the regulatory effect of NG on TSLP-induced mast cell proliferation and inflammatory reactions using human mast cell line (HMC-1) cells. HMC-1 cells were pre-treated with NG and then treated with TSLP. HMC-1 cells proliferation was determined by quantifying bromodeoxyuridine incorporation. Levels of anti-apoptotic and pro-apoptotic factors were analyzed by western blot analysis. The productions and mRNA expressions of interleukin (IL)-13 and tumour necrosis factor-α (TNF-α) were analyzed by ELISA and quantitative real-time PCR. We found that NG significantly attenuated HMC-1 cells proliferation and Ki-67 mRNA expression promoted by TSLP. NG significantly suppressed mRNA expression of TSLP receptor and IL-7 receptor α in TSLP-treated HMC-1 cells. NG significantly down-regulated levels of phosphorylated-signal transducer and activation of transcription 6 and murine double-minute 2 in TSLP-treated HMC-1 cells, up-regulated levels of cleaved poly ADP-ribose polymerase and p53 in TSLP-treated HMC-1 cells. Furthermore, NG significantly decreased the productions and mRNA expressions of IL-13 and TNF-α in TSLP-treated HMC-1 cells. These results suggest NG has an inhibitory effect on mast cell-mediated allergic inflammatory reactions.

Chrysin attenuates atopic dermatitis by suppressing inflammation of keratinocytes

We previously reported the inhibitory effect of chrysin, a natural flavonoid plentifully contained in propolis, vegetables and fruits, on the mast cell-mediated allergic reaction. In this study, we evaluated the effect of chrysin on atopic dermatitis (AD) and defined underlying mechanisms of action. We used an AD model in BALB/c mice by the repeated local exposure of 2,4-dinitrochlorobenzene (DNCB) and house dust mite (Dermatophagoides farinae extract, DFE) to the ears. Repeated alternative treatment of DNCB/DFE caused AD-like skin lesions. Oral administration of chrysin diminished AD symptoms such as ear thickness and histopathological analysis, in addition to serum IgE and IgG2a levels. Chrysin decreased infiltration of mast cells, and reduced serum histamine level. Chrysin also suppressed AD by inhibiting the inflammatory responses of Th1, Th2, and Th17 cells in mouse lymph node and ear. Interestingly, chrysin significantly inhibited the production of cytokines, Th2 chemokines, CCL17 and CCL22 by the down-regulation of p38 MAPK, NF-κB, and STAT1 in tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT). Chrysin also inhibited TNF-α/IFN-γ-stimulated IL-33 expression in HaCaT cells and mouse primary keratinocytes. Taken together, the results indicate that chrysin suppressed AD symptoms, suggesting that chrysin might be a candidate for the treatment of AD and skin allergic diseases.

Erratum: 2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the FcεRI signaling pathway.

Erratum: 2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the FcεRI signaling pathway.

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.

2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the FcεRI signaling pathway.

Mast cells are important effector cells in immunoglobulin (Ig) E-mediated allergic reactions such as asthma, atopic dermatitis and rhinitis. Vanillic acid, a natural product, has shown anti-oxidant and anti-inflammatory activities. In the present study, we investigated the anti-allergic inflammatory effects of ortho-vanillic acid (2-hydroxy-3-methoxybenzoic acid, o-VA) that was a derivative of vanillic acid isolated from Amomum xanthioides. In mouse anaphylaxis models, oral administration of o-VA (2, 10, 50 mg/kg) dose-dependently attenuated ovalbumin-induced active systemic anaphylaxis and IgE-mediated cutaneous allergic reactions such as hypothermia, histamine release, IgE production and vasodilation; administration of o-VA also suppressed the mast cell degranulator compound 48/80-induced anaphylaxis. In cultured mast cell line RBL-2H3 and isolated rat peritoneal mast cells in vitro, pretreatment with o-VA (1-100 μmol/L) dose-dependently inhibited DNP-HSA-induced degranulation of mast cells by decreasing the intracellular free calcium level, and suppressed the expression of pro-inflammatory cytokines TNF-α and IL-4. Pretreatment of RBL-2H3 cells with o-VA suppressed DNP-HSA-induced phosphorylation of Lyn, Syk, Akt, and the nuclear translocation of nuclear factor-κB. In conclusion, o-VA suppresses the mast cell-mediated allergic inflammatory response by blocking the signaling pathways downstream of high affinity IgE receptor (FcεRI) on the surface of mast cells.

The role of thymic stromal lymphopoietin on mast cell-mediated allergic inflammatory reactions

Thymic stromal lymphopoietin (TSLP) is a novel interleukin (IL)-7-like cytokine and was originally discovered in the supernatant of a murine thymic stromal cell line. TSLP signal initiates via complex of the TSLP receptor and the IL-7 receptor α chain. TSLP expression is closely connected with many diseases such as atopic dermatitis, allergic rhinitis, asthma, inflammatory arthritis, eosinophilic esophagitis, rheumatoid arthritis, inflammatory bowel diseases, and cancer. In this review, I discussed biological roles of TSLP on mast cell-mediated allergic responses. In addition, this review summarizes the effective drugs in allergic-inflammatory reactions induced by TSLP on mast cells.

Inhibitory effects of atractylone on mast cell-mediated allergic reactions

This study investigated a salutary effect of atractylone (Atr) which is an active constituent of Pyeongwee-San (KMP6) on mast cell-mediated allergic reactions. Our previous report indicated that KMP6 regulated allergic reactions. Thus, this study sought to determine the potential of Atr in vitro models, compound 48/80-stimulated rat peritoneal mast cells (RPMCs), phorbol 12-myristate 13-acetate (PMA) plus A23187-stimulated human mast cell line (HMC-1) cells, and stem cell factor (SCF)-stimulated RPMCs as well as in vivo models, IgE-mediated passive cutaneous anaphylaxis (PCA), compound 48/80-induced systemic anaphylaxis, and compound 48/80-induced ear swelling. The results showed that Atr inhibited compound 48/80-induced RPMCs degranulation, intracellular calcium level, tryptase release, and histamine release. Atr inhibited the up-regulation of p56lck tyrosine kinase activity by compound 48/80. And Atr reduced tryptase and histamine releases from PMA plus A23187-stimulated HMC-1 cells. In addition, Atr decreased histidine decarboxylase activity and expression in the activated HMC-1 cells. Atr inhibited SCF-induced morphological alteration and filamentous actin formation in RPMCs. Atr improved IgE-induced PCA reaction by decreasing the levels of histamine, IgE, interleukin (IL)-4, IL-5, IL-6, vascular endothelial growth factor, and IL-13 in the serum of PCA-induced mice. Furthermore, Atr mitigated compound 48/80-induced systemic anaphylaxis and ear swelling. Taken together, these results of this study indicate that Atr regulates the degranulation of mast cell, proving its potential in the treatment of mast cell-mediated allergic reactions.