[Show abstract][Hide abstract] ABSTRACT: In recent years, it is recognized that acquired immunity is controlled by regulatory T cell (Treg). Since fundamental pathophysiological changes of allergy are mainly caused by hyperresponsiveness of immune system to allergens that acquires after birth, Tregs likely play key roles in the pathogenesis of allergy, particularly during the sensitization phase. However, accumulated information indicate that there are several distinctive subtypes of Tregs in man, and each of them seems to play different role in controlling immune system, which complicates the involvement of Tregs in allergy. The aim of the present study is to attempt to classify subtypes of Tregs and summarize their roles in allergy. Tregs should include natural Tregs (nTreg) including inducible costimulator (ICOS)(+) Tregs, inducible/adaptive Tregs (iTreg), interleukin (IL)-10-producing type 1 Tregs (Tr1 cells), CD8(+) Tregs and IL-17-producing Tregs. These cells share some common features including expression of Foxp3 (except for Tr1 cells), and secretion of inhibitory cytokine IL-10 and/or TGF-beta. Furthermore, it is noticeable that Tregs likely contribute to allergic disorders such as dermatitis and airway inflammation, and play a crucial role in the treatment of allergy through their actions on suppression of effector T cells and inhibition of activation of mast cells and basophils. Modulation of functions of Tregs may provide a novel strategy to prevent and treat allergic diseases.
Journal of Translational Medicine 05/2014; 12(1):125. · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine-induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease.
[Show abstract][Hide abstract] ABSTRACT: Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process of inflammation including exudation of plasma components, inflammatory cell infiltration, and tissue damage and repair, PARs appear to make important contribution to allergy. The aim of the present review is to summarize the expression of PARs in inflammatory and structural cells, the influence of agonists or antagonists of PARs on cell behavior, and the involvement of PARs in allergic disorders, which will help us to better understand the roles of serine proteases and PARs in allergy.
Mediators of Inflammation 01/2014; 2014:829068. · 2.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Protease-activated receptor 2 (PAR-2), which is abundantly expressed in astrocytes, is known to play major roles in brain inflammation. However, the influence of the natural agonist of PAR-2, tryptase, on proinflammatory mediator releasedfrom astrocytes remains uninvestigated. In the present study, we found that tryptase at lower concentrations modestly reduced intracellular ROS production but significantly increased IL-6 and TNF- α secretion at higher concentrations without affecting astrocytic viability and proliferation. The actions of tryptase were alleviated by specific PAR-2 antagonist FSLLRY-NH2 (FS), indicating that the actions of tryptase were via PAR-2. PI3K/AKT inhibitor LY294002 reversed the effect of tryptase on IL-6 production, whereas inhibitors specific for p38, JNK, and ERK1/2 abolished the effect of tryptase on TNF- α production, suggesting that different signaling pathways are involved. Moreover, tryptase-induced activation of MAPKs and AKT was eliminated by FS, implicating that PAR-2 is responsible for transmitting tryptase biosignals to MAPKs and AKT. Tryptase provoked also expression of TGF- β and CNTF in astrocytes. The present findings suggest for the first time that tryptase can regulate the release of cytokines from astrocytes via PAR-2-MAPKs or PAR-2-PI3K/AKT signaling pathways, which reveals PAR-2 as a new target actively participating in the regulation of astrocytic functions.
Mediators of Inflammation 01/2013; 2013:140812. · 2.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allergic diseases are major diseases involving approximately 22% of world population. In recent years, accumulated evidence suggests that apart from IgE, allergens may provoke immediate allergic reactions via other pathways such as IgG, toll like receptor (TLR) dependent ones. In addition, large numbers of low molecular weight molecules (LMWM) such as sphingosine-1-phosphate and iodinated contrast agents have been observed to cause allergy. Therefore, the current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions. Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these cells, we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions, whereas IgE only serves as one of the activators of these cells.
Current Molecular Medicine 08/2012; · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: The prevalence of allergic diseases has increased dramatically in recent decades. Therefore, there is a pressing need for the development of effective anti-allergic services worldwide. AREAS COVERED: In previous studies, the authors had analyzed a total of 789 anti-allergic patents granted in China from 1988 to 2008. Herein, they report a further 151 anti-allergic patents issued in China during 2009 - 2011. The current analysis covers the scientific progress in supporting anti-allergic patent applications and granted patent literature, in China, for the last 3 years. EXPERT OPINION: The 151 anti-allergic patents granted from 2009 to 2011 mainly focus on seven types of products. They are: traditional Chinese medicines (TCM), plant extracts, biological products, synthetic compounds, pharmaceutical preparations, medical apparatus and new treatment modalities. Although the overall number of anti-allergic patent applications made between 2009 and 2011 in China is less than that of the USA and Europe, patents on TCM have increased. This suggests that there are demands for modernization of TCMs. Recently, studies of interesting new immunomodulators have also been conducted, and some of these are likely to represent clinically useful advances. In the last 3 years, several patents on these novel potential drugs have also been granted in China. The large number of anti-allergic patents issued in China, in recent times, suggests that the Chinese market is relatively competitive one that will help pharmaceutical companies make proper decisions for their research and development strategies.
[Show abstract][Hide abstract] ABSTRACT: Mast cell tryptase can stimulate peripheral mononuclear cells activation to cause widespread inflammation. However, the influence of tryptase on microglia, the resident immune cells in the brain, remains uninvestigated. Since microglia plays a pivotal role in immune surveillance of CNS, we studied the effect of tryptase on microglia activation.
Induction of microglia activation by tryptase was examined with primary cultured microglia. TNF-alpha and IL-6 was measured with a commercial ELISA kit. Intracellular ROS was determined by dichlorodihydrofluorescein oxidation. Mitochondrial membrane potential was assessed with the MitoProbe™ JC-1 assay kit. And MAPK and NF-kappa B phosphorylation were evaluated by Western blot.
We found that tryptase stimulated microglia activation and subsequently produced proinflammatory factors TNF-alpha, IL-6 and ROS. Inhibition of PAR-2 activation reduced tryptase-induced TNF-alpha, IL-6 and ROS production, and mitochondrial membrane potential loss in microglia. Among the three members of MAPK pathway, ERK and p38, but not JNK mediated tryptase-induced microglia activation. Inhibition of PAR-2 suppressed tryptase-induced ERK and p38 MAPK pathway activation in microglia. Tryptase also activated NF-kappa B within 30 min, and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF- kappa B, reduced tryptase-induced TNF-alpha and IL-6 release.
Our results suggest that tryptase can induce microglia activation and pro-inflammatory mediator release via PAR-2-MAPK-NF-kappa B signaling pathway, which will contribute to the development of microglia-mediated inflammation in brain.
Cellular Physiology and Biochemistry 01/2012; 29(5-6):931-40. · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tryptic enzymes, including tryptase, a signature enzyme in mast cells, are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic inflammatory airway disease. However, the relationship between tryptase enzyme activity and COPD remains to be investigated. We therefore measured the enzyme activity and immunoreactivity of tryptase in the sputum and plasma of COPD patients in the present study. The results showed that tryptase enzyme activity in the sputum of severe COPD patients (FEV(1)s being recorded at ≤ 30% prediction values) was 3.4 times greater than that in patients with mild COPD (FEV(1)s being recorded at ≥ 80% of predicted values), whereas tryptic activity was 2.0 times higher in the severe COPD patients than in mild COPD patients. Moreover, tryptase enzyme activity, but not tryptic enzyme activity, was significantly elevated in the plasma of severe COPD patients compared with that of mild COPD patients. The level of immunoreactive tryptase was 1.9 times higher in the sputum of the severe COPD patients at admission than that at remission stage. We also employed a rat model of cigarette smoke-induced COPD. After 36 weeks of daily challenges with cigarette smoke, a well-established risk factor of COPD, tryptic and tryptase activities in the bronchoalveolar lavage fluid were elevated 1.5 and 2.6 times, respectively. These results indicate that smoking induces tryptase enzyme activity in the airway. In conclusion, tryptase enzyme activity is markedly increased in sputum and plasma of severe COPD patients. Enhanced tryptase enzyme activity may contribute to the pathogenesis of COPD.
The Tohoku Journal of Experimental Medicine 01/2011; 224(3):179-87. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prevalence of allergic diseases has increased dramatically in recent decades. Therefore, there is a pressing need for the development of effective anti-allergic services worldwide. However, little is known what anti-allergic products have been patented in China and what the potential drug candidates for patents are in China.
To analyze the patents of anti-allergic products for the last 20 years and help pharmaceutical companies and individuals to understand the potential candidates for anti-allergic patents in China.
Data were obtained from the People's Republic of China Country Intellectual Property Rights Bureau website and United States Patent and Trademark Office website. Results: A total of 789 anti-allergic patents have been granted in China during the past 20 years, which all focused on synthetic compounds, traditional Chinese medicines (TCM), combinations of synthetic compounds and TCM, biological products and medical apparatus. It appears that more and more effective therapeutic components of TCM rather than whole herbs have been patented in recent years and alteration of natural molecules to produce more therapeutically effective molecules has emerged as a novel trend for the modernization of TCM. The patents on synthetic anti-allergic compounds in China mainly focus on well-known targets, such as histamine receptor and leukotrienes, which consist of 93% of patents for validated targets.
The number of anti-allergic patents applied in China is far lower than that in the US. Therefore, there are great opportunities for obtaining anti-allergic patents, particularly patents on active ingredients from TCM in China.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of allergic diseases has increased dramatically in recent decades. Holding patents is one of the means to protect good anti-allergy products. However, little is known of anti-allergy patent situation in China. The paper summarized and analyzed anti-allergy patents issued in China from January 1988 to September 2008. A total of 789 anti-allergy patents have been granted in China during the 20 years. China, European countries, USA, Japan and other countries possesses 44%, 21%, 19%, 12% and 4% of all of these anti-allergy patents respectively. Interestingly, 88% anti-allergy patents issued to Chinese are held by civilians, whereas vast majority of the patents issued to foreigners were held by pharmaceutical companies. All anti-allergy patents are focused on synthetic compounds, Traditional Chinese Medicines (TCM),combinations of synthetic compounds and TCM (CST), biological products and medical apparatus. The anti-allergy patents in China mainly focus on well-known targets, such as histamine receptor and leukotrienes, which consist of 93% of patents for validated targets. Approximately 93% targeting diseases are bronchial asthma, allergic rhinitis and atopic dermatitis. Our analyzing results indicate that there are great opportunities for application of patents on development of novel anti-allergic compounds and modernization of TCM in China.
Recent Patents on Inflammation & Allergy Drug Discovery 06/2010; 4(2):130-7.