Hyun-A Oh

TSLP induces mast cell development and aggravates allergic reactions through the activation of MDM2 and STAT6.

Thymic stromal lymphopoietin (TSLP) is known to promote T helper type 2 cell-associated inflammation. Mast cells are major effector cells in allergic inflammatory responses. We noted that the population and maturation of mast cells were reduced in TSLP-deficient mice (TSLP-/-). Thus, we hypothesized that TSLP might affect mast cell development. We found that TSLP induced the proliferation and differentiation of mast cells from bone marrow progenitors. TSLP-induced mast cell proliferation was abolished by depletion of mouse double minute 2 (MDM2) and signal transducers and activators of transcription 6 (STAT6), as an upstream activator of MDM2. TSLP-/-, in particular, had a considerable deficit in the expression of MDM2 and STAT6. Also, the TSLP deficiency attenuated mast cell-mediated allergic reactions through the downregulation of STAT6 and MDM2. In an antibody microarray chip analysis, MDM2 expression was increased in atopic dermatitis patients. These observations indicate that TSLP is a factor for mast cell development, and that it aggravates mast cell-mediated immune responses.

IL-32 up-regulation is associated with inflammatory cytokine production in allergic rhinitis.

IL‐32 is a described pro‐inflammatory cytokine produced by T lymphocytes, natural killer cells, monocytes, and epithelial cells. However, the specific mechanism of IL‐32 on allergic rhinitis (AR) has not been elucidated. Here, we report a significant increase of IL‐32 protein and mRNA in the nasal mucosa of AR patients. In addition, in nasal mucosa tissue from AR patients, the level of IL‐32 production correlated with inflammation, IL‐1β, IL‐18, and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). In an AR animal model, IL‐32 significantly increased IgE and inflammatory cytokine levels. IL‐32 expression was induced by recombinant human GM‐CSF via activation of caspase‐1 in eosinophils. In addition, depletion of IL‐32 prevents the production of inflammatory cytokines in eosinophils. In conclusion, IL‐32 is an important cytokine involved in the inflammation of AR. The regulation of IL‐32 expression may form the basis of a new strategy for the treatment of AR. Copyright

The critical role of mast cell-derived hypoxia-inducible factor-1α in human and mice melanoma growth

Mast cells play an important role in tumorigenesis. Histamine released from mast cells stimulates new vessel formation by acting through the histamine1 (H1) receptor. Despite the evidence of the role of mast cells in tumor growth and angiogenesis, the potential mechanism remains to be elucidated. Therefore, we investigated the role of mast cell‐derived HIF‐1α in melanoma growth. Here, we identify that the most positive cells for HIF‐1α staining are seen in mast cells of human and animal melanoma tissue. The number of the stromal cell types (fibroblasts, macrophages and endothelial cells) was also increased in melanoma tissues. In activated bone marrow‐derived mast cells (BMMCs), expressions of HIF‐1α and VEGF were increased. Histamine also induced the expressions of HIF‐1α and VEGF in BMMCs. H1 receptor antagonists significantly improved overall survival rates and substantially suppressed tumor growth as well as the infiltration of mast cells and levels of VEGF through the inhibition of HIF‐1α expression in B16F10 melanoma‐bearing mice. Furthermore, the injection of HIF‐1α depleted BMMCs markedly inhibited the growth of tumors and migration of mast cells and increased the survival rate of the mice. These findings emphasize that the growth of melanoma can actually be exacerbated by mast cell‐derived HIF‐1α. In aggregate, our results reveal a novel role for mast cell‐derived HIF‐1α in the melanoma microenvironment and have important implications for the design of therapeutic strategies.

Interleukin-32-induced thymic stromal lymphopoietin plays a critical role in macrophage differentiation through the activation of caspase-1 in vitro.

IntroductionInterleukin (IL)-32 is an inflammatory cytokine induced by Mycobacterium tuberculosis and Mycobacterium bovis in a variety of cell types and discovered in the synovial of patients with rheumatoid arthritis (RA). Thymic stromal lymphopoietin (TSLP) play several roles in the pathogenesis of RA. However, the role of IL-32 and TSLP in RA has not been elucidated.MethodsWe evaluated the specific mechanism of between IL-32 and TSLP in RA using human monocyte cell line, THP-1 cells.ResultsHere we documented for the first time that IL-32 highly increased TSLP production in THP-1 cells and human blood monocytes. TSLP expression was induced by IL-32 via activation of caspase-1 and nuclear factor-κB. TSLP produced by IL-32 increased differentiation of monocytes but depletion of TSLP prevented differentiation of monocytes into macrophage-like cells. Chondroprotective drugs such as chondroitin sulfate (CS) and the traditional Korean medicine, BaekJeol-Tang (BT) decrease production of TSLP and activation of caspase-1 and nuclear factor-κB. In addition, CS and BT inhibited IL-32-induced monocytes differentiation.ConclusionsTaken together, IL-32 and TSLP are important cytokines involved in the development of RA. The effects of CS and BT were associated with the downregulation of TSLP and caspase-1 through negative regulation of IL-32 pathways in RA.

Beneficial effects of chelidonic acid on a model of allergic rhinitis

Chelidonic acid (CA) is known as an inhibitor of the rat brain glutamate decarboxylase. However, the pharmacological effects of CA in allergic reactions have not yet been defined. Here, we show the effects and the mechanism of CA in the ovalbumin (OVA)-sensitized allergic rhinitis (AR) model. CA significantly decreased the number of nasal/ear rubs and increment of IgE levels in the AR mice. The level of interferon-γ was enhanced while the level of IL-4 was reduced on the spleen tissue of the CA-administered AR mice. Expressions of IL-1β and cyclooxygenase-2 were inhibited by CA administration in the nasal mucosa tissues. Infiltration of eosinophils and mast cells was decreased in the CA-administered AR mice. Furthermore, CA decreased the caspase-1 activity in the same nasal mucosa tissue and human mast cell line, HMC-1. Our results indicate that CA may attenuate allergic reaction by inhibition of caspase-1 activity.

Alleviation of allergic rhinitis symptoms with Pyeongwee-San extract (KMP6)

Context: Allergy is characterized by the overreaction of the immune system. Pyeongwee-San is a traditional Korean medicine which has been used for the treatment of the allergic disorder but the mechanism of action is not clear. Objective: To investigate the effect of Pyeongwee-San extract (KMP6) and its component, hesperidin (HES) in the allergic rhinitis (AR) animal model. Method: We sensitized mice on 1, 5, and 14 days by intraperitoneal injections of 100 μg ovalbumin (OVA) emulsified in 20 mg of aluminum hydroxide and we challenged mice with 1.5 mg OVA. Mice received KMP6 and HES before the intranasal OVA challenge for 10 days. Results: The number of nose rubs after the OVA challenge in the OVA-sensitized mice was significantly higher than that in the OVA-unsensitized mice. The increased number of nose rub was inhibited by the oral administration of KMP6 or HES. The increased levels of IgE and histamine level in serum of the OVA-sensitized mice were reduced by KMP6 or HES administration. The level of interferon-γ was enhanced while the level of IL-4 was reduced on the spleen tissue of the KMP6 or HES-administered AR mice. Inflammatory proteins level was reduced by KMP6 or HES administration in the nasal mucosa tissue of the OVA-sensitized mice. In the KMP6 or HES-administered mice, mast cells and eosinophils infiltration increased by OVA-sensitization was decreased. Conclusion: These results indicate that KMP6 and HES ameliorate the allergic inflammatory reactions such as AR.

Heat-processed ginseng saponin ameliorates the adenine-induced renal failure in rats

To evaluate the effect of the saponin of heat-processed ginseng (Sun ginseng, SG), we investigated the protective effect of SG total saponin fraction against adenine-induced chronic renal failure in rats. SG saponin significantly decreased the levels of urea nitrogen and creatinine in the serum, but increased the urinary excretion of urea nitrogen and creatinine, indicating an improvement of renal function. SG saponin also inhibited adenine-induced kidney hypertrophy and edema. SG saponin reduced serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase activities increased by adenine. Based on these findings, the ameliorating effect of SG on chronic renal failure may result from its saponin.

Ginsenoside Rg1 inhibits the TSLP production in allergic rhinitis mice

Abstract Recent study reports that Korean red ginseng reduces the nasal allergic inflammatory reaction in an allergic murine model. However, the contribution of ginsenoside Rg1 (RG1) and its mechanisms on allergic rhinitis (AR) have not been elucidated. In this study, we evaluated the important activities of RG1 in the ovalbumin (OVA)-induced AR mice. RG1 significantly reduced the levels of thymic stromal lymphopoietin (TSLP) and interleukin (IL)-1β compared with the AR control mice. Allergic symptom such as rub scores and biomarkers such as spleen weight, histamine, IgE and IgG1 in the RG1 group were decreased compared with the AR mice. The levels of interferon-γ were enhanced while the levels of IL-4 were reduced in the RG1 group. In the RG1 group, the eosinophils and mast cells infiltration increased by OVA were also decreased. RG1 reduced the levels of inflammation-related protein. RG1 inhibited the caspase-1 activity in nasal mucosa tissue. In addition, RG1 inhibited the production of TSLP and IL-1β and the activations of caspase-1, receptor interacting protein 2, IκB kinase-β and nuclear factor-κB/Rel A in activated HMC-1 cells. Our results indicate that RG1 has the inhibitory effect of TSLP production and caspase-1 activity in AR experimental model.

Inhibition of IL-32 and TSLP production through the attenuation of caspase-1 activation in an animal model of allergic rhinitis by Naju Jjok (Polygonum tinctorium)

In this study, we investigated the effects of Naju Jjok (Polygonum tinctorium Lour., NJJ) on interleukin (IL)-32 and thymic stromal lymphopoietin (TSLP) levels associated with allergic rhinitis (AR). Using female BALB/c mice, we created an animal model of ovalbumin (OVA)-induced AR. Prior to the callenge with OVA, the mice were administered, either nasally or orally with NJJ. In addition, we also used the eosinophilic cells line, Eol-1, stimulated with granulocyte‑macrophage colony-stimulation factor (GM-CSF). The mRNA and protein levels of inflammatory cytokines and markers [interleukin (IL)-32, IL-4, macrophage-inflammatory protein-2 (MIP-2), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2)] were measured by RT-PCR and western blot analysis, respectively and serum levels were measured by ELISA. The increased levels of IL-32 in the mice with AR and in the stimulated eosinophilic cell line, Eol-1, were significantly reduced by NJJ. TSLP levels were also decreased following the oral administration of NJJ. Mice orally administered NJJ showed markedly alleviated clinical symptoms, such as a reduced number of nasal rubs, decreased spleen weight, decreased serum immunoglobulin E (IgE) levels and decreased serum histamine levels. The oral administration of NJJ significantly decreased the IL-4 levels, while increasing the interferon-γ levels in the spleen. The increased number of eosinophils and mast cells infiltrating the nasal mucosal tissue of the mice with AR were decreased following the oral administration of NJJ. NJJ effectively attenuated caspase-1 activity in the mice with AR and in the stimulated Eol-1 cells. The oral administration of NJJ significantly reduced the levels of inflammatory markers, such as MIP-2, ICAM-1 and COX-2. Furthermore, the intranasal administration of NJJ significantly reduced the early phase response to allergen exposure, such as nasal rubs, IgE production and histamine release, as well as the late phase responses, such as the expression of inflammatory markers. In conclusion, these data demonstrate that NJJ may play a regulatory role in nasal inflammation.

Evaluation of the effect of kaempferol in a murine allergic rhinitis model.

Kaempferol (KP) is a major compound of Naju Jjok (Polygonum tinctorium Lour.). The effect of KP on allergic rhinitis (AR) has not been elucidated. Here, we report the effects and mechanisms of KP on new and predominant mediators of AR using an eosinophil cell line, Eol-1 and an ovalbumin (OVA)-induced AR mouse model. KP significantly inhibited the production of interleukin (IL)-32 and IL-8 and activation of caspase-1 in Eol-1 cells. Allergic symptoms and predominant mediators (IgE and histamine) in the KP-administered group were significantly lower than in the AR group. The levels of interferon-γ were enhanced while the levels of IL-4 were reduced in the KP group. KP significantly reduced the levels of IL-32 and thymic stromal lymphopoietin (TSLP) compared with the AR mice. KP reduced the levels of inflammation-related proteins. In the KP-administered groups, the infiltrations of eosinophils and mast cells increased by OVA were decreased. In addition, KP significantly reduced caspase-1 activity in nasal mucosa tissue of AR mice. Our findings indicate that KP has an anti-allergic effect through the regulation of the production of IL-32 and TSLP and caspase-1 activity in allergic diseases including AR.