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IL-3 and TNFα increase Thymic Stromal Lymphopoietin Receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation
Ellen B Cook, James L Stahl, Elizabeth A Schwantes, Kristen E Fox, Sameer K Mathur
Clinical and Molecular Allergy , 2012, DOI: 10.1186/1476-7961-10-8
Abstract: Eosinophil mRNA expression of TSLPR and IL-7Rα was examined by real-time quantitative PCR of human eosinophils treated with TNFα and IL-5 family cytokines, and TSLPR surface expression on eosinophils was analyzed by flow cytometry. Eosinophils were stimulated with TSLP (with and without pre-activation with TNFα and IL-3) and evaluated for release of eosinophil derived neurotoxin (EDN), phosphorylation of STAT5, and survival by trypan blue exclusion. A blocking antibody for TSLPR was used to confirm the specificity of TSLP mediated signaling on eosinophil degranulation.Eosinophil expression of cell surface TSLPR and TSLPR mRNA was upregulated by stimulation with TNFα and IL-3. TSLP stimulation resulted in release of EDN, phosphorylation of STAT5 as well as promotion of viability and survival. TSLP-stimulated eosinophil degranulation was inhibited by a functional blocking antibody to TSLPR. Pre-activation of eosinophils with TNFα and IL-3 promoted eosinophil degranulation at lower concentrations of TSLP stimulation.This study demonstrates that eosinophils are activated by TSLP and that eosinophil degranulation in response to TSLP may be enhanced on exposure to cytokines present in allergic inflammation, indicating that the eosinophil has the capacity to participate in TSLP-driven allergic responses.Thymic stromal lymphopoietin (TSLP) is a cytokine which plays a key role in allergic diseases such as asthma, atopic dermatitis, allergic rhinitis, nasal polyposis, and chronic allergic keratoconjunctivis [1-5]. TSLP is a member of the hematopoietic cytokine family that includes a number of cytokines important in allergic disease including IL-2, IL-4, IL-7, and IL-13. TSLP binds with high affinity to a heterodimeric receptor consisting of the IL-7 receptor - alpha chain (IL-7Rα) and TSLPR (TSLP receptor also known as cytokine receptor-like 2, CRL2). As a member of the hematopoietin receptor family, signaling through activation of TSLPR results in downstream phosphorylation
Eosinophils Increase Neuron Branching in Human and Murine Skin and In Vitro  [PDF]
Erin L. Foster,Eric L. Simpson,Lorna J. Fredrikson,James J. Lee,Nancy A. Lee,Allison D. Fryer,David B. Jacoby
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022029
Abstract: Cutaneous nerves are increased in atopic dermatitis, and itch is a prominent symptom. We studied the functional interactions between eosinophils and nerves in human and mouse skin and in culture. We demonstrated that human atopic dermatitis skin has eosinophil granule proteins present in the same region as increased nerves. Transgenic mice in which interleukin-5 (IL-5) expression is driven by a keratin-14 (K14) promoter had many eosinophils in the epidermis, and the number of nerves was also significantly increased in the epidermis. In co-cultures, eosinophils dramatically increased branching of sensory neurons isolated from the dorsal root ganglia (DRG) of mice. This effect did not occur in DRG neurons co-cultured with mast cells or with dead eosinophils. Physical contact of the eosinophils with the neurons was not required, and the effect was not blocked by an antibody to nerve growth factor. DRG neurons express eotaxin-1, ICAM-1 and VCAM-1, which may be important in the recruitment, binding, and activation of eosinophils in the region of cutaneous nerves. These data indicate a pathophysiological role for eosinophils in cutaneous nerve growth in atopic dermatitis, and suggest they may present a therapeutic target in atopic dermatitis and other eosinophilic skin conditions with neuronal symptoms such as itch.
The IL-1-Like Cytokine IL-33 Is Constitutively Expressed in the Nucleus of Endothelial Cells and Epithelial Cells In Vivo: A Novel ‘Alarmin’?  [PDF]
Christine Moussion, Nathalie Ortega, Jean-Philippe Girard
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003331
Abstract: Background Interleukin-33 (IL-33) is an IL-1-like cytokine ligand for the IL-1 receptor-related protein ST2, that activates mast cells and Th2 lymphocytes, and induces production of Th2-associated cytokines in vivo. We initially discovered IL-33 as a nuclear factor (NF-HEV) abundantly expressed in high endothelial venules from lymphoid organs, that associates with chromatin and exhibits transcriptional regulatory properties. This suggested that, similarly to IL-1α and chromatin-associated cytokine HMGB1, IL-33 may act as both a cytokine and a nuclear factor. Although the activity of recombinant IL-33 has been well characterized, little is known yet about the expression pattern of endogenous IL-33 in vivo. Methodology/Principal Findings Here, we show that IL-33 is constitutively and abundantly expressed in normal human tissues. Using a combination of human tissue microarrays and IL-33 monoclonal and polyclonal antibodies, we found that IL-33 is a novel nuclear marker of the endothelium widely expressed along the vascular tree. We observed abundant nuclear expression of IL-33 in endothelial cells from both large and small blood vessels in most normal human tissues, as well as in human tumors. In addition to endothelium, we also found constitutive nuclear expression of IL-33 in fibroblastic reticular cells of lymphoid tissues, and epithelial cells of tissues exposed to the environment, including skin keratinocytes and epithelial cells of the stomach, tonsillar crypts and salivary glands. Conclusions/Significance Together, our results indicate that, unlike inducible cytokines, IL-33 is constitutively expressed in normal human tissues. In addition, they reveal that endothelial cells and epithelial cells constitute major sources of IL-33 in vivo. Based on these findings, we speculate that IL-33 may function, similarly to the prototype ‘alarmin’ HMGB1, as an endogenous ‘danger’ signal to alert the immune system after endothelial or epithelial cell damage during trauma or infection.
The Alarmin Concept Applied to Human Renal Transplantation: Evidence for a Differential Implication of HMGB1 and IL-33  [PDF]
Antoine Thierry, Sébastien Giraud, Aurélie Robin, Anne Barra, Franck Bridoux, Virginie Ameteau, Thierry Hauet, Jean-Philippe Girard, Guy Touchard, Jean-Marc Gombert, André Herbelin
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088742
Abstract: The endogenous molecules high mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been identified as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. We analysed serum and urinary HMGB1 and IL-33 levels, all determined by enzyme-linked immunosorbent assay, in a cohort of 26 deceased renal transplant recipients. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to those before treatment. Moreover, both serum and urinary IL-33 (but not HMGB1) increase was positively correlated with cold ischemia time, from 30 min to 3 days post-transplantation. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Finally, we postulate that leukocytes from renal recipient patients are targeted by both HMGB1 and IL-33, as suggested by increased transcription of their respective receptors (TLR2/4 and ST2L) shortly after transplantation. Consistent with this view, we found that iNKT cells, an innate-like T cell subset involved in IRI and targeted by IL-33 but not by HMGB1 was activated 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans.
Topical Application of Chrysanthemum indicum L. Attenuates the Development of Atopic Dermatitis-Like Skin Lesions by Suppressing Serum IgE Levels, IFN-γ, and IL-4 in Nc/Nga Mice
Sunmin Park,Jung Bok Lee,Suna Kang
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/821967
Abstract: Chrysanthemum indicum L. (CIL) is widely used as an anti-inflammatory agent in Asia and our preliminary study revealed that CIL reduced interleukin (IL)-4 and IL-13 in 2,4-dinitrochlorobenzene (DNCB)-treated HaCaT cells, a human keratinocyte cell line. We investigated the atopic dermatitis (AD) effect of topically applied CIL in mice with AD-like symptoms. After topical application of 1,3-butylen glycol (control), CIL-Low (5%), CIL-High (30%), or 0.1% hydrocortisone (HC) on the AD-like skin lesions in DNCB-treated NC/Nga mice for 5 weeks, the ear thickness, mast cell infiltration, and serum immunoglobulin E (IgE), IgG1, IL-4 and interferon (IFN)-γ were measured. The gene expressions of IL-4, IL-13, and IFN-γ in the dorsal skin were assayed. CIL treatment dosedependently reduced severity of clinical symptoms of dorsal skin, ear thickness, and the number of mast cells and eosinophils. CIL-High significantly decreased serum IgE, IgG1, IL-4, and IFN-γ levels and reduced mRNA levels of IFN-γ, IL-4, and IL-13 in dorsal skin lesion. The improvement by CIL-High was similar to HC, but without its adverse effects such as skin atrophy maceration, and secondary infection. In conclusion, CIL may be an effective alternative substance for the management of AD.
Serum Levels of Il-8, Tnf-α And Il-6 in Children with Atopic Dermatitis  [cached]
Perihan ?ztürk,Murat Aral,Ergül Belge Kuruta?,Ekrem Kire??i
Güncel Pediatri , 2012,
Abstract: In-tro-duc-ti-on: Atopic dermatitis (AD) is associated with an imbalance between T helper 1 (Th1) and T helper 2 (Th2) cells. It is chronic relapsing inflammatory skin disease affecting especially the children. Recently, it has been intensively studied and new aspects regarding the immunopathogenesis are suggested. Studies about the role of cytokines on formation of atopic diseases are rather new and most of them are based on in vitro observations. It is not completely clear yet how cytokines regulate diseases in vivo and studies about this subject are rather limited. In this study; the serum levels of IL-8, TNF-α, IL-6 and the relationship between these parameters and the disease severity in a group of children with AD were investigated.Materials and Methods: The severity of AD was assessed by the same dermatologist using the Scoring Atopic Dermatitis (SCORAD) index system. IL-8, TNF-α, and IL-6 levels were measured by ELISA method.Results: Serum levels of IL-8, TNF-α and IL-6 were determined and were found statistically significantly higher in patients than controls. A statistically significant correlation between serum levels of IL-8, TNF-α, and IL-6 and SCORADs in children with AD was determined.Conclusion: These results show that serum levels of IL-8, TNF-α, and IL-6 may be used as important markers in the assessment of disease severity and follow-up of child patients with AD. As a result, the role of cytokines and the relationship between cytokines in the immunopathogenesis of AD are rather complex and still not clearly clarified, further investigations are required to understand this complex process. (Jo-ur-nal of Cur-rent Pe-di-at-rics 2012; 10: 50-4)
The Effect of PPAR Agonists on the Migration of Mature and Immature Eosinophils  [PDF]
Steven G. Smith,Haruki Imaoka,Neha Punia,Anam Irshad,Luke L. Janssen,Roma Sehmi,Gail M. Gauvreau
PPAR Research , 2012, DOI: 10.1155/2012/235231
Abstract: PPARγ agonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis) and random cell movement (chemokinesis). To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα, δ, and γ agonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγ agonist), GW9578 (PPARα agonist), GW501516 (PPARδ agonist), or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils ( ), and SDF-1α-induced migration of immature eosinophils ( ). Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration ( ). The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function. 1. Introduction Eosinophils are effector cells which contribute to the pathology of allergic diseases [1]. They are recruited from the blood into inflamed tissue by local release of chemokines [2, 3]. Eotaxin-1, which is one of the most potent eosinophil chemokines, signals through chemokine receptor 3 (CCR3). Novel approaches toward inhibiting migration of effector cells such as eosinophils are being investigated for treatment of allergic asthma. The peroxisome proliferator-activated receptors (PPARs) are metabolite-activated transcription factors that have been shown to regulate metabolic and inflammatory responses [4]. There are three identified subtypes of PPARs: PPARα [5], PPARγ [6], and PPARδ [7], which have attracted interest as therapeutic targets in lung disease due to their preferential expression on human airway smooth muscle [8] and inflammatory cells [9] and increased expression during inflammatory events [10, 11]. In murine models of allergic asthma, PPARα and PPARγ agonists (rosiglitazone and GW9578, resp.) inhibit eosinophil influx to the lung following airway antigen challenge [12, 13]. The PPARγ agonist was more effective than the PPARα agonist, while the PPARδ agonist had no
The glucocorticoid RU24858 does not distinguish between transrepression and transactivation in primary human eosinophils
Mirkka Janka-Junttila, Eeva Moilanen, Hannele Hasala, Xianzhi Zhang, Ian Adcock, Hannu Kankaanranta
Journal of Inflammation , 2006, DOI: 10.1186/1476-9255-3-10
Abstract: Human peripheral blood eosinophils were isolated under sterile conditions and cultured in the presence and/or absence RU24858. For comparison, dexamethasone and mometasone were used. We measured chemokine receptor-4 (CXCR4) and Annexin 1 expression by flow cytometry and cytokine production by ELISA. Apoptosis was measured by DNA fragmentation and confirmed by morphological analysis.RU24858 (1 μM) increased CXCR4 and Annexin 1 expression on eosinophils to a similar extent as mometasone (1 μM) and dexamethasone (1 μM). Like dexamethasone and mometasone, RU24858 did suppress IL-8 and MCP-1 production in eosinophils. RU24858 also increased spontaneous eosinophil apoptosis to a similar degree as dexamethasone and mometasone, but unlike dexamethasone and mometasone it did not reverse IL-5- or GM-CSF-induced eosinophil survival.Our results suggest that in human eosinophils RU24858 acts as transactivator and transrepressor like classical glucocorticoids. Thus, RU24858 seems not to be a "dissociated steroid" in primary human eosinophils in contrast to that reported in animal cells. In addition, functionally RU24858 seems to be a less potent glucocorticoid as it did not reverse IL-5- and GM-CSF-afforded eosinophil survival similarly to dexamethasone and mometasone.Eosinophils are thought to play a critical role in allergic diseases, such as allergic rhinitis, asthma, and atopic dermatitis.[1] In patients with asthma, activation of eosinophils is thought to cause epithelial tissue injury, and increased bronchial responsiveness.[2] Apoptosis or programmed cell death is an important feature in the resolution of pulmonary inflammation.[3,4] Unlike necrosis which is characterized by loss of cell membrane integrity and the uncontrolled release of harmful cellular contents, apoptosis is characterized by formation of apoptic bodies, which are then phagocytosed intact so there will be no leakage of intracellular contents or activation of the inflammatory response.[3,5] Eosinophil apop
IL-13 expression by blood T cells and not eosinophils is increased in asthma compared to non-asthmatic eosinophilic bronchitis
Salman Siddiqui, Glenn Cruse, Susan Mckenna, William Monteiro, Vijay Mistry, Andrew Wardlaw, Christopher Brightling
BMC Pulmonary Medicine , 2009, DOI: 10.1186/1471-2466-9-34
Abstract: We sought to examine IL-13 expression in peripheral blood T-cells and eosinophils in asthma and non-asthmatic eosinophilic bronchitis. Peripheral blood CD3+ cell and eosinophil intracellular IL-13 expression from subjects with asthma, non-asthmatic eosinophilic bronchitis and healthy controls was assessed. The effect of priming by asthmatic serum on the release of IL-13 by peripheral blood mononuclear cells from healthy subjects was examined and the serum from these subjects was analysed for a range of chemokines and cytokines.The median (IQR)% intracellular IL-13 expression by CD3+ cells was increased in asthma [5.3 (2.7–9.8)%; n = 12] compared to non-asthmatic eosinophilic bronchitis [1.1 (0.5–3)%; n = 7] and healthy controls [1.7 (0.2–3%); n = 9] (p = 0.02), but was not significantly different in eosinophils across the groups. IL-13 released from healthy peripheral blood mononuclear cells (n = 10) was increased by asthmatic serum [117 (47.8–198)pg/ml] compared to control [78.5 (42.6–128)pg/ml; p = 0.02), but was not affected by non-asthmatic serum.Our findings support the view that IL-13 expression is increased in peripheral blood-derived T cells in asthma and that asthmatic serum up-regulates IL-13 release from healthy peripheral blood mononuclear cells.Asthma is characterised by the presence of variable airflow obstruction, airway hyper-responsiveness (AHR), and an airway inflammatory response often characterised by Th2-mediated eosinophilic airway inflammation [1] with mast cell infiltration of the airway smooth muscle (ASM) bundle[2]. The Th2 cytokine interleukin (IL)-13 has been implicated in the pathogenesis of asthma[3]. Its central role in the asthma paradigm is supported by human studies that have reported increased IL-13 mRNA expression in bronchial biopsies from subjects with moderate asthma[4,5] and from sputum cells from corticosteroid na?ve and inhaled corticosteroid treated asthmatics[6]. In addition, following allergen challenge in mild asthmatics
Effects of dexamethasone on TNF-alpha-induced release of cytokines from purified human blood eosinophils
Iain Uings, Ilaria Puxeddu, Vladislav Temkin, Susan J Smith, Dilniya Fattah, Keith P Ray, Francesca Levi-Schaffer
Clinical and Molecular Allergy , 2005, DOI: 10.1186/1476-7961-3-5
Abstract: The effect of dexamethasone on TNF-alpha induced eosinophils survival, degranulation (ECP), cytokines release (IL-8, GM-CSF) and adhesion to VCAM-1, ICAM-1 and IgG coated wells (EPO release) were evaluated.The drug inhibited IL-8 and GM-CSF production, but not viability, degranulation or adhesion in human peripheral blood eosinophils.These results indicate that part of the activity of glucocorticosteroids on eosinophils may be mediated by their ability to inhibit cytokine secretion that in turn is important for the perpetuation of the allergic inflammation.Eosinophils are bone marrow-derived granulocytes that play a crucial role in allergic inflammation. TNF-α is a pro-inflammatory cytokine synthesized by many inflammatory and structural cells. We previously demonstrated that mast cell-derived TNF-α induced eosinophil survival by autocrine production of GM-CSF [1]. TNF-α is also involved in eosinophil adhesion to endothelial cells and induces eosinophil activation, degranulation, and cytokines production. Glucocorticosteroids (GCS), the main anti-inflammatory drugs in allergic diseases, have been demonstrated to decrease circulating and tissue eosinophils. In vitro dexamethasone can inhibit eosinophil survival [2], expression of adhesion molecules [3], and cytokines production [4]. However, the effect of GCS on TNF-α induced eosinophil activation has only been partially investigated. The present study evaluated the effect of dexamethasone on TNF-α induced eosinophil degranulation, cytokines release and adhesion to VCAM-1, ICAM-1 and IgG.Eosinophils were purified (>95%) from the peripheral blood of healthy non-atopic volunteers as previously described [5]. Freshly isolated eosinophils (viability >98%) were cultured in 96 well flat bottom tissue culture plates (Costar, High Wycombe, UK) (1.5 × 105/200 μl/well) in RPMI-1640 supplemented with 10% heat inactivated foetal calf serum (FCS) containing 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin in the
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