scholarly journals Histamine-Releasing Factor, a New Therapeutic Target in Allergic Diseases

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1515 ◽  
Author(s):  
Yu Kawakami ◽  
Kazumi Kasakura ◽  
Toshiaki Kawakami
Keyword(s):  
Recombinant Proteins ◽  
Complex Disease ◽  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Ige Mediated ◽  
Human Basophils ◽  
Type 2 Inflammation

Histamine-releasing activities on human basophils have been studied as potential allergy-causing agents for four decades. An IgE-dependent histamine-releasing factor (HRF) was recently shown to interact with a subset of immunoglobulins. Peptides or recombinant proteins that block the interactions between HRF and IgE have emerged as promising anti-allergic therapeutics, as administration of them prevented or ameliorated type 2 inflammation in animal models of allergic diseases such as asthma and food allergy. Basic and clinical studies support the notion that HRF amplifies IgE-mediated activation of mast cells and basophils. We discuss how secreted HRF promotes allergic inflammation in vitro and in vivo complex disease settings.

scholarly journals An epithelial microRNA upregulates airway IL-25 and TSLP expression in type 2-high asthma via targeting CD39-extracellular ATP axis

2020 ◽  
Author(s):  
Kan Zhang ◽  
Yuchen Feng ◽  
Yuxia Liang ◽  
Wenliang Wu ◽  
Chenli Chang ◽  
...  
Keyword(s):  
Allergic Diseases ◽  
Lavage Fluid ◽  
Extracellular Atp ◽  
Lymphoid Cells ◽  
Healthy Controls ◽  
Asthma Patients ◽  
Type 2 Inflammation

ABSTRACTIntroductionEpithelial cell-derived cytokines IL-25, IL-33 and TSLP initiate type 2 inflammation in allergic diseases. However, the signaling pathway regulating these cytokines expression remains elusive. We examined the role of epithelial microRNAs in the expression of IL-25, IL-33 and TSLP in asthma.MethodsDifferentially expressed epithelial microRNAs between type 2-low and type 2-high asthma patients were identified using microarray. The expression of microRNA (miR)-206, its target CD39, CD39’s substrate ATP, and IL-25, IL-33, TSLP were measured in epithelial brushings and bronchoalveolar lavage fluid from both asthma subsets and healthy controls. The links between these measurements were functionally validated in vitro and in vivo.ResultsMiR-206 was the most highly expressed microRNA in type 2-high asthma relative to type 2-low asthma, but was downregulated in both asthma subsets compared with healthy controls. CD39, an ecto-nucleotidase degrading ATP, was a target of miR-206 and upregulated in asthma. Allergen-induced acute extracellular ATP accumulation led to miR-206 downregulation and CD39 upregulation in human bronchial epithelial cells, forming a feedback loop to eliminate excessive ATP. Airway ATP levels strongly correlated with elevated IL-25 and TSLP expression in type 2-high asthma patients. Intriguingly, airway miR-206 antagonism increased Cd39 expression, reduced ATP accumulation, suppressed Il-25, Il-33, Tslp expression and group 2 innate lymphoid cells expansion, and alleviated type 2 inflammation in a mouse model of asthma. However, airway miR-206 overexpression had opposite effects.ConclusionTogether, epithelial miR-206 upregulates airway IL-25, TSLP expression via targeting CD39-extracellular ATP axis, which represents a novel therapeutic target in type 2-high asthma.

The Biologic Role of Interleukin-8: Functional Analysis and Expression of CXCR1 and CXCR2 on Human Eosinophils

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 694-702
Author(s):  
Holger Petering ◽  
Otto Götze ◽  
Daniela Kimmig ◽  
Regina Smolarski ◽  
Alexander Kapp ◽  
...  
Keyword(s):  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Interleukin 8 ◽  
Cytokine Activation ◽  
Cc Chemokines ◽  
Eosinophil Granulocytes ◽  
In Vitro Effects

Chemokines play an important role in attracting granulocytes into sites of inflammation. Two chemokine subfamilies differ in their biologic activity for different granulocyte subsets. Whereas CXC chemokines such as interleukin-8 (IL-8) activate predominantly neutrophils, CC chemokines such as RANTES and eotaxin activate predominantly eosinophils. However, controversial results have been published in the past regarding the biologic role of IL-8 in eosinophil activation, particularly in allergic diseases. In this study, we investigated the functional evidence and expression of both IL-8 receptors, CXCR1 and CXCR2, on highly purified human eosinophils. In the first set of experiments, a chemotaxis assay was performed showing that IL-8 did not induce chemotaxis of eosinophils. In addition, and in contrast to neutrophils and lymphocytes, IL-8 did not induce a rapid and transient release of cytosolic free Ca2+([Ca2+]i) in eosinophils, even after preincubation with TH1- and TH2-like cytokines. To investigate whether neutrophil contamination might be responsible for the reported IL-8 effects on eosinophils, neutrophils were added to highly purified eosinophils from the same donor in different concentrations. Interestingly, as little as 5% of neutrophil contamination was sufficient to induce an increase of [Ca2+]iafter stimulation with IL-8. Flow cytometry experiments with monoclonal antibodies against both IL-8 receptors demonstrated no expression of CXCR1 and CXCR2 on eosinophils before or after cytokine activation. Reverse transcriptase-polymerase chain reaction experiments showed that eosinophils, in contrast to neutrophils and lymphocytes, did not express mRNA for CXCR1 and CXCR2. In summary, this study clearly demonstrates that CXCR1 and CXCR2 are not expressed on human eosinophils, even after priming with different bioactive cytokines. Because the CXC chemokine IL-8 did not induce in vitro effects on human eosinophils, IL-8 may also not contribute in vivo to the influx of eosinophil granulocytes into sites of allergic inflammation. Our results suggest that CC chemokines such as eotaxin, eotaxin-2, and MCP-4 are predominant for the activation of eosinophils.

scholarly journals Association between Type 2 Diabetes, Obesity and Key Immunological Components of IgE-mediated Inflammation

Folia Medica ◽  
2017 ◽  
Vol 59 (2) ◽  
pp. 159-164 ◽  
Author(s):  
Raditsa N. Sokolova ◽  
Rumyana K. Yankova ◽  
Tsvetana I. Abadjieva ◽  
Tatyana A. Popova ◽  
Maria V. Ivanovska ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Serum Levels ◽  
Total Serum ◽  
Control Group ◽  
Serum Ige ◽  
Ige Mediated

AbstractBackground:Changes in lifestyle and obesity in recent decades have brought about a dramatic increase in type 2 diabetes mellitus (DM2) and allergic diseases. Clinical and epidemiological studies associate obesity with epidemics of allergic diseases. The link between obesity and DM2 with immunological components of IgE-mediated allergic inflammation is not yet conclusively established.Aim:To examine the key immunological components of IgE-mediated allergic inflammation in patients with DM2 and their relationship with glycemic control and anthropometric indicators.Materials and methods:Fifty-five patients with DM2 and 32 healthy controls with normal weight and body mass index (BMI) of 18-24.9 kg/m2were included in the study. Th2-cytokine profile (serum levels of IL-4 and IL-5, pg/ml) and total serum IgE IU/ml were assessed in all participants in the study using ELISA. In patients with DM2, levels of glycated hemoglobin (HbA1c%) in the blood were also measured.Results:Serum levels of IL-4 and IL-5 are significantly higher in patients with DM2 compared to the control group. Serum levels of IL-4 and IL-5 positively correlated with BMI as well as serum levels of IL-4 with waist circumference. Total serum IgE positively correlated with HbA1c.Conclusion:Obesity and poor glycemic control in patients with DM2 affect key immunological components of IgE-mediated allergic inflammation and possibly alter the immune response to allergens and antigens.

Granzyme B, a novel mediator of allergic inflammation: its induction and release in blood basophils and human asthma

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2290-2299 ◽  
Author(s):  
Cornelia M. Tschopp ◽  
Nicole Spiegl ◽  
Svetlana Didichenko ◽  
Werner Lutmann ◽  
Peter Julius ◽  
...  
Keyword(s):  
De Novo ◽  
Granzyme B ◽  
Allergic Inflammation ◽  
Allergen Challenge ◽  
Allergic Diseases ◽  
Cytotoxic Lymphocytes ◽  
Leukotriene C4 ◽  
Granzyme A

Abstract Histamine, leukotriene C4, IL-4, and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the makeup of granules of human basophils by inducing de novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6 to 24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and -independent activation. In vitro, there is a close parallelism between GzmB, IL-13, and leukotriene C4 production. In vivo, granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.

The Biologic Role of Interleukin-8: Functional Analysis and Expression of CXCR1 and CXCR2 on Human Eosinophils

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 694-702 ◽  
Author(s):  
Holger Petering ◽  
Otto Götze ◽  
Daniela Kimmig ◽  
Regina Smolarski ◽  
Alexander Kapp ◽  
...  
Keyword(s):  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Interleukin 8 ◽  
Cytokine Activation ◽  
Cc Chemokines ◽  
Eosinophil Granulocytes ◽  
In Vitro Effects

Abstract Chemokines play an important role in attracting granulocytes into sites of inflammation. Two chemokine subfamilies differ in their biologic activity for different granulocyte subsets. Whereas CXC chemokines such as interleukin-8 (IL-8) activate predominantly neutrophils, CC chemokines such as RANTES and eotaxin activate predominantly eosinophils. However, controversial results have been published in the past regarding the biologic role of IL-8 in eosinophil activation, particularly in allergic diseases. In this study, we investigated the functional evidence and expression of both IL-8 receptors, CXCR1 and CXCR2, on highly purified human eosinophils. In the first set of experiments, a chemotaxis assay was performed showing that IL-8 did not induce chemotaxis of eosinophils. In addition, and in contrast to neutrophils and lymphocytes, IL-8 did not induce a rapid and transient release of cytosolic free Ca2+([Ca2+]i) in eosinophils, even after preincubation with TH1- and TH2-like cytokines. To investigate whether neutrophil contamination might be responsible for the reported IL-8 effects on eosinophils, neutrophils were added to highly purified eosinophils from the same donor in different concentrations. Interestingly, as little as 5% of neutrophil contamination was sufficient to induce an increase of [Ca2+]iafter stimulation with IL-8. Flow cytometry experiments with monoclonal antibodies against both IL-8 receptors demonstrated no expression of CXCR1 and CXCR2 on eosinophils before or after cytokine activation. Reverse transcriptase-polymerase chain reaction experiments showed that eosinophils, in contrast to neutrophils and lymphocytes, did not express mRNA for CXCR1 and CXCR2. In summary, this study clearly demonstrates that CXCR1 and CXCR2 are not expressed on human eosinophils, even after priming with different bioactive cytokines. Because the CXC chemokine IL-8 did not induce in vitro effects on human eosinophils, IL-8 may also not contribute in vivo to the influx of eosinophil granulocytes into sites of allergic inflammation. Our results suggest that CC chemokines such as eotaxin, eotaxin-2, and MCP-4 are predominant for the activation of eosinophils.

scholarly journals Pathological Roles and Clinical Usefulness of Periostin in Type 2 Inflammation and Pulmonary Fibrosis

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1084
Author(s):  
Junya Ono ◽  
Masayuki Takai ◽  
Ayami Kamei ◽  
Yoshinori Azuma ◽  
Kenji Izuhara
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Biological Fluids ◽  
Allergic Inflammation ◽  
Transforming Growth Factor Β ◽  
Serum Levels ◽  
Vital Role ◽  
Interleukin 4 ◽  
Type 2 Inflammation

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-β, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.

scholarly journals Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2545
Author(s):  
Ya-Hui Chen ◽  
Po-Hui Wang ◽  
Pei-Ni Chen ◽  
Shun-Fa Yang ◽  
Yi-Hsuan Hsiao
Keyword(s):  
Cervical Cancer ◽  
Potential Role ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Anticancer Effects ◽  
Clinical Benefits ◽  
Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

scholarly journals Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 268
Author(s):  
Jonathan Ribot ◽  
Cyprien Denoeud ◽  
Guilhem Frescaline ◽  
Rebecca Landon ◽  
Hervé Petite ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Therapeutic Modality ◽  
Multipotent Stromal Cells ◽  
Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

scholarly journals 3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics

2021 ◽  
Vol 22 (6) ◽  
pp. 2925
Author(s):  
Victor Häussling ◽  
Romina H Aspera-Werz ◽  
Helen Rinderknecht ◽  
Fabian Springer ◽  
Christian Arnscheidt ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
In Vitro Model ◽  
Bone Diseases ◽  
3D Environment ◽  
Type 2 Diabetics ◽  
Mineralized Matrix ◽  
Vitro Model

A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common complications in diabetics. However, there is still a lack of advanced strategies to treat diabetic bone diseases. To develop such therapeutic strategies, mechanisms leading to massive bone alterations in diabetics have to be well understood. We herein describe an in vitro model displaying bone metabolism frequently observed in diabetics. The model is based on osteoblastic SaOS-2 cells, which in direct coculture, stimulate THP-1 cells to form osteoclasts. While in conventional 2D cocultures formation of mineralized matrix is decreased under pre-/diabetic conditions, formation of mineralized matrix is increased in 3D cocultures. Furthermore, we demonstrate a matrix stability of the 3D carrier that is decreased under pre-/diabetic conditions, resembling the in vivo situation in type 2 diabetics. In summary, our results show that a 3D environment is required in this in vitro model to mimic alterations in bone metabolism characteristic for pre-/diabetes. The ability to measure both osteoblast and osteoclast function, and their effect on mineralization and stability of the 3D carrier offers the possibility to use this model also for other purposes, e.g., drug screenings.

scholarly journals Antidiabetic Properties of Naringenin: A Citrus Fruit Polyphenol

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 99 ◽  
Author(s):  
Danja J. Den Hartogh ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Animal Studies ◽  
Citrus Fruit ◽  
Epidemiological Studies ◽  
Personal Health ◽  
Current Review ◽  
Vegetables And Fruits

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and hyperglycemia and is associated with personal health and global economic burdens. Current strategies/approaches of insulin resistance and T2DM prevention and treatment are lacking in efficacy resulting in the need for new preventative and targeted therapies. In recent years, epidemiological studies have suggested that diets rich in vegetables and fruits are associated with health benefits including protection against insulin resistance and T2DM. Naringenin, a citrus flavanone, has been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, immunomodulatory and antidiabetic properties. The current review summarizes the existing in vitro and in vivo animal studies examining the anti-diabetic effects of naringenin.

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