BACKGROUND: Interleukin-5 (IL-5) is responsible for eosinophilia in allergic diseases. In allergic bronchial asthma, there is a correlation between the extent of eosinophil infiltration in bronchial mucosa and IL-5 concentrations. In addition, IL-2 concentration is elevated in the airways and associated with eosinophilia in symptomatic patients with bronchial asthma. In animal studies, IL-2 can induce eosinophilia by increasing the synthesis of IL-5, however, it is still unknown how IL-2 can induce eosinophila in human being. The aim of this study is to evaluation the effect and mechanism of IL-2 on prolongation of eosinophil survival. METHODS: After purifiing the eosinophils from the venous blood of allergic patients with eosinophilia, we measured the survival rates of eosinophils using trypan blue dye exclusion test, and the number of eosinophils with Randolp's solution. We compared the survival rates of eosinophils in the presence of IL-2 or IL-5. Neutralizing antibody for IL-5 was added in IL-2 treated eosinophils to reveal whether IL-2 induced prolongation of eosinophil survival was mediated by IL-5. We checked IL-5 m-RNA expression of lymphocytes in the presence of IL-2 by using Reverse transcription-Polymerase chain reaction (RT-PCR) method to revealed the effect of IL-2 on IL-5 m-RNA expression on lymphocyte. alpha and beta IL-2 receptors were measured on eosinophils and lymphocytes with flow-cytometer after stimulated with IL-2. RESULTS: 1) Eosinophil survival rates increased dose dependently on IL-5 and IL-2. 2) The eosinophil survival rates increased by IL-2 were not inhibited by the pretreatment with neutralizing antibody for IL-5. 3) IL-5 m-RNA was not expressed on lymphocytes by the treatment with IL-2 up to 96 hours. 4) IL-2 upregulate the expression of IL-2Ralpha on eosinophils, instead of no effect on the expression of IL-2Rbeta. CONCLUSION: Interleukin-2 had the enhancing effect on the survival rates of eosinophils. The mechanism behind IL-2 induced eosinophilia might be the increment of IL-2 receptors on eosinophils rather than IL-5 synthesis by lymphocytes.
Animals ; Antibodies, Neutralizing ; Asthma ; Eosinophilia ; Eosinophils* ; Humans ; Interleukin-2 ; Interleukin-2 Receptor alpha Subunit ; Interleukin-5 ; Lymphocytes ; Mucous Membrane ; Receptors, Interleukin-2 ; Survival Rate ; Trypan Blue

Eosinophilia is common feature of many disorders, including allergic diseases. There are many factors that influence the production, migration, survival and death of the eosinophil. Apoptosis is the most common form of physiological cell death and a necessary process to maintain but limit cell numbers in humans and other species. It has been directly demonstrated that eosinophil apoptosis is delayed in allergic inflammatory sites, and that this mechanism contributes to the expansion of eosinophil numbers within tissues. Among the proteins known to influence hematopoiesis and survival, expression of the cytokine interleukin-5 appears to be uniquely important and specific for eosinophils. In contrast, eosinophil death can result from withdrawal of survival factors, but also by activation of pro-apoptotic pathways via death factors. Recent observations suggest a role for cell surface death receptors and mitochondria in facilitating eosinophil apoptosis, although the mechanisms that trigger each of these death pathways remain incompletely delineated. Ultimately, the control of eosinophil apoptosis may someday become another therapeutic strategy for treating allergic diseases and other eosinophil-associated disorders.
Apoptosis ; Cell Count ; Cell Death ; Eosinophilia ; Eosinophils ; Hematopoiesis ; Humans ; Interleukin-5 ; Mitochondria ; Proteins ; Receptors, Death Domain

Eosinophilia is common feature of many disorders, including allergic diseases. There are many factors that influence the production, migration, survival and death of the eosinophil. Apoptosis is the most common form of physiological cell death and a necessary process to maintain but limit cell numbers in humans and other species. It has been directly demonstrated that eosinophil apoptosis is delayed in allergic inflammatory sites, and that this mechanism contributes to the expansion of eosinophil numbers within tissues. Among the proteins known to influence hematopoiesis and survival, expression of the cytokine interleukin-5 appears to be uniquely important and specific for eosinophils. In contrast, eosinophil death can result from withdrawal of survival factors, but also by activation of pro-apoptotic pathways via death factors. Recent observations suggest a role for cell surface death receptors and mitochondria in facilitating eosinophil apoptosis, although the mechanisms that trigger each of these death pathways remain incompletely delineated. Ultimately, the control of eosinophil apoptosis may someday become another therapeutic strategy for treating allergic diseases and other eosinophil-associated disorders.
Apoptosis ; Cell Count ; Cell Death ; Eosinophilia ; Eosinophils ; Hematopoiesis ; Humans ; Interleukin-5 ; Mitochondria ; Proteins ; Receptors, Death Domain

PURPOSE: In the Phase III SIROCCO trial (NCT01928771), benralizumab significantly reduced asthma exacerbations and improved lung function and symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate efficacy and safety of benralizumab for Korean patients in SIROCCO. METHODS: SIROCCO was a randomized, double-blind, parallel-group, placebo-controlled trial of 1,204 patients aged 12–75 years with severe asthma uncontrolled by high-dosage inhaled corticosteroids/long-acting β2-agonists (ICS/LABA). Patients received benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W; first 3 doses Q4W) or placebo Q4W for 48 weeks. The primary analysis population comprised patients with blood eosinophil counts ≥ 300 cells/µL. This subgroup analysis evaluated Korean patients from this group. RESULTS: Of 122 Korean patients randomized, 86 had blood eosinophil counts ≥ 300 cells/µL. Benralizumab reduced the annual asthma exacerbation rate by 70% (Q4W: rate estimate 0.79, rate ratio 0.30 [95% confidence interval {CI}, 0.13–0.65], nominal P = 0.003; n = 28) and 85% (Q8W: rate estimate 0.40, rate ratio 0.15 [95% CI, 0.06–0.36], nominal P < 0.001; n = 30) vs. placebo (rate estimate 2.67, n = 28). Prebronchodilator forced expiratory volume in 1 second was increased with benralizumab treatment by 0.270 L (Q4W: 95% CI, 0.039–0.500, nominal P = 0.023; n = 28) and 0.362 L (Q8W: 95% CI, 0.143–0.582, nominal P = 0.002; n = 30) vs. placebo (n = 27). Total asthma symptom score was similar for patients receiving either benralizumab Q4W (−0.27 [95% CI, −0.83 to 0.30], nominal P = 0.356; n = 27) or benralizumab Q8W (0.10 [95% CI, −0.44 to 0.65], nominal P = 0.708; n = 30) vs. placebo (n = 28). Drug-related adverse events were experienced by 2%, 8%, and 5% of patients in the placebo, benralizumab Q4W, and benralizumab Q8W arms. CONCLUSIONS: Benralizumab reduced annual asthma exacerbation rates, increased lung function, and was well-tolerated by Korean patients with severe, uncontrolled eosinophilic asthma.
Arm ; Asthma ; Eosinophils ; Forced Expiratory Volume ; Humans ; Korea ; Lung ; Receptors, Interleukin-5

Interleukin-5 (IL-5), which is known to be an activator of human eosinophil, increases in IgA nephropathy. In order to find out the relationship between activated eosinophil function and the pathogenesis of Henoch-Sch nlein purpura (HSP) and IgA nephropathy, serum esosinophil cationic protein (ECP) was analyzed using a monoclonal antibody Besides, the soluble IL-2 receptor (sIL-2R) was analyzed to clarify if there was a positive correlation between T cells and activated eosinophils. As anticipated, the levels of ECP, in detail, were significantly higher among HSP patients with a mean of 9.7+/-1.8microgram/L than in a control group with a mean of 4.6+/-0.7microgram/L. The HSP patients were also classified as one group with normal urine and another group with abnormal urine. The latter showed higher levels of ECP than the former. On the other hand, the levels of ECP were higher in IgA nephropathy patients than in the control group; however, there was no significance in statistics. The sIL-2R levels were higher in HSP patients than those in serums of IgA nephropathy patients and the control group. Thus, this study came to a conclusion that the activated eosinophil might be one of the pathogeneses in HSP but not in IgA nephropathy.
Eosinophil Cationic Protein* ; Eosinophils* ; Glomerulonephritis, IGA* ; Hand ; Humans ; Immunoglobulin A* ; Interleukin-5 ; Purpura ; Receptors, Interleukin-2 ; T-Lymphocytes

Asthma, remains symptomatic despite ongoing treatment with high doses of inhaled corticosteroids (ICS) in conjunction with long-acting beta-agonists (LABA), is classified as “severe” asthma. In the course of caring for those patients diagnosed with severe asthma, stepping up from ICS/LABA to more aggressive therapeutic measures would be justified, though several aspects have to be checked in advance (including inhaler technique, adherence to therapy, and possible associated comorbidities). That accomplished, it would be advisable to step up care in accordance with the Global Initiative for Asthma (GINA) recommendations. Possible strategies include the addition of a leukotriene receptor antagonist or tiotropium (to the treatment regimen). The latter has been shown to be effective in the management of several subgroups of asthma. Oral corticosteroids have commonly been used for the treatment of patients with severe asthma in the past; however, the use of oral corticosteroids is commonly associated with corticosteroid-related adverse events and comorbidities. Therefore, according to GINA 2017 these patients should be referred to experts who specialize in the treatment of severe asthma to check further therapeutic options including biologics before starting treatment with oral corticosteroids.
Adrenal Cortex Hormones ; Asthma ; Biological Products ; Comorbidity ; Humans ; Immunoglobulin E ; Interleukin-5 ; Nebulizers and Vaporizers ; Receptors, Leukotriene ; Tiotropium Bromide

BACKGROUND: Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling. METHODS: BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M2 and M3 receptors were examined. RESULTS: Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M2 but decreased expression of M3 in all aged groups of OVA. CONCLUSION: Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M3 and M2 muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.
Actins ; Aged ; Airway Remodeling ; Animals ; Asthma* ; Eosinophils ; Female ; Humans ; Hydroxyproline ; Interleukin-13 ; Interleukin-5 ; Interleukins ; Mice* ; Ovalbumin ; Ovum ; Pneumonia ; Receptors, Muscarinic* ; Tiotropium Bromide*

BACKGROUND: Irradiation of the skin with ultraviolet rays result in alterations of immune response as well as melanogenesis and melanocarcinogenensis. These effects are largely mediated by soluble mediators released from epidermal cells in response to ultraviolet rays. OBJECTIVE: To evaluate the effect of ultraviolet B (UVB) irradiation on the normal human melanocyte gene expression. METHODS: We demonstrated genes modulated by UVB irradiation among over 300 genes coding CDs, cytokins, growth factors, and growth factor receptors in normal human melanocytes by cDNA microarray technique. RESULTS: Two genes out of 384 genes in cultured normal human melanocytes were found up-regulated following UVB irradiation. They are the genes coding lactotransferrin and CD160. Forty one genes out of 384 genes were found down-regulated by UVB irradiation. They included the genes coding IL-9, IL-5, TNF-alpha, TNF-beta, IL-6 receptor and CD20. CONCLUSION: These results provide the basis for future studies on the immunologic role in modulated genes by UV-stressed human melanocytes.
Clinical Coding ; Gene Expression ; Humans* ; Intercellular Signaling Peptides and Proteins ; Interleukin-5 ; Interleukin-9 ; Lactoferrin ; Lymphotoxin-alpha ; Melanocytes* ; Oligonucleotide Array Sequence Analysis ; Receptors, Growth Factor ; Receptors, Interleukin-6 ; Skin ; Tumor Necrosis Factor-alpha ; Ultraviolet Rays

BACKGROUNDAsthma is clinically related with the degree of eosinophilic inflammation. How asthmatic airway inflammation is affected is still poorly understood. So the effects of bone marrow-derived hematopoietic cells expressing CD(34) (CD(34)(+)) and interleukin-5 (IL-5) receptor messenger RNA (IL-5R mRNA+) on asthmatic airway inflammation were investigated.

METHODSBalb/c mice were sensitized and challenged by ovalbumin (OVA) to establish an asthmatic model while control mice were sensitized and exposed to sterile saline. The mice were killed at different time points after being challenged by OVA and sterile saline. Then, bronchoalveolar lavage fluid (BALF), peripheral blood (PB) and bone marrow (BM) were prepared. Eosinophils in PB (PBEOS) and BALF (BALFEOS), nuclear cells in BALF, PB and BM were counted. By flow cytometry, the percentage of CD(34)(+) cells to nucleated cells in PB, BM and the relative number of CD(34)(+) cells in PB (PBCD(34)(+)) and BM (BMCD(34)(+)) were calculated. Immunocytochemistry and in situ hybridization were used to investigate the hematopoietic cells with co-localized expression of CD(34) and IL-5R mRNA in BM (BMCD34+IL-5R mRNA+). The percentage of BMCD34+IL-5R mRNA+ to BMCD(34)(+) was calculated.

RESULTSTwelve hours after challenge by OVA, BALFEOS and PBEOS in the experimental group were significantly higher than those in the control group (P < 0.01). Twenty-four hours after OVA challenge, BALFEOS, PBEOS and BMCD34+IL-5R mRNA+ were elevated maximally, significantly different from those in the control group (P < 0.01). Forty-eight hours after OVA challenge, BALFEOS and BMCD34+IL-5R mRNA+ were still significantly higher than those of the controls (P < 0.01). The other markers reverted to normal. In 60 mice, BMCD34+IL-5R mRNA+ was closely correlated with the BALEOS, PBEOS, BMCD(34)(+) and BMCD(34)(+) (%) (P < 0.05).

CONCLUSIONSThe amount of CD(34)(+) cells expressing IL-5R mRNA increased in the BM of asthmatic model mice, which favors eosinophilopoiesis and eosinophilic airway inflammation. A signal pathway exists between the lungs and the bone marrow, which is involved in the initiation and maintenance of asthmatic airway inflammation.

Animals ; Antigens, CD34 ; analysis ; Asthma ; immunology ; Bone Marrow Cells ; cytology ; Bronchoalveolar Lavage Fluid ; cytology ; Inflammation ; immunology ; Male ; Mice ; Mice, Inbred BALB C ; RNA, Messenger ; analysis ; Receptors, Interleukin ; genetics ; Receptors, Interleukin-5

BACKGROUND AND OBJECTIVES: Mammalian Toll-like receptors (TLR) participate in innate immune responses to microbial pathogens. Recent interest has been focused on the concept that TLR-induced innate responses can modulate subsequent adaptive immune responses. The objective of this study is to determine whether TLR 2 stimulation in vivo would modulate subsequent allergic responses in an Aspergillus fumigatus (Af) murine model of allergic rhinitis (AR). MATERIALS AND METHOD: Mice were sensitized via intraperitoneal injection with Af antigen and alum, and received a series of three daily intranasal Af antigen challenge. A TLR 2 agonist, PamCys was administrated intranasally one day before sensitization or one day before the first intranasal allergen challenge. Adaptive immune profiles and response to Af challenge were assessed. RESULTS: PamCys decreased the allergen induced nasal recruitment of eosinophils and interleukin (IL)-5 in nasal lavage fluids compared with mice treated with no PamCys. Serologic data revealed that PamCys downregulated Af-specific IgE in the sera of PamCys-treated mice. In addition, spleen cells from the PamCys-treated mice displayed attenuated Af-specific IL-4 and IL-5, but increased interferon (IFN)- and immunosuppressive IL-10. CONCLUSION: The present study demonstrate that TLR 2 agonist decreases allergic responses in this AR model by shifting T helper 2 (Th2) biased immune parameters towards Th1 dominance.
Animals ; Aspergillus fumigatus ; Bias (Epidemiology) ; Eosinophils ; Immunity, Innate ; Immunoglobulin E ; Injections, Intraperitoneal ; Interferons ; Interleukin-10 ; Interleukin-4 ; Interleukin-5 ; Interleukins ; Mice* ; Models, Animal ; Nasal Lavage Fluid ; Rhinitis* ; Spleen ; Toll-Like Receptor 2* ; Toll-Like Receptors*