The Role and Molecular Mechanism of Interleukin-17A in Innate Immunity and Allergic Response in Human Airway Epithelium PDF Download

Author: Fei Huang
Publisher:
ISBN:
Category :
Languages : en
Pages : 226

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Author: Cheng-Yuan Kao
Publisher:
ISBN:
Category :
Languages : en
Pages : 378

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Author: Valérie Quesniaux
Publisher: Springer Science & Business Media
ISBN: 3764386819
Category : Medical
Languages : en
Pages : 247

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Book Description
The IL-17 cytokines represent a novel family of cytokines, which defines a new effector T cell, the Th17 cell, and extend the Th1-Th2 paradigm. Th17 cells in part co-express at least IL-17A and IL-17F, IL-21 and IL-22. IL-17 A/F are produced by T cells ( and ), iNKT cells, and possibly neutrophils, dendritic cells and Paneth cells. The regulation of IL-17 family member’s expression, and the identification of effector mechanisms are an area of intense current research. Recognized regulators of IL-17A expression include the nuclear receptor ROR t, proinflammatory cyt- ines such as IL-1, IL-6 with TGF- , IL-21, IL-23 IL-25 in the absence of IFN- and IL-4, which are discussed. Recent data suggest that IL-17A may have a dual fu- tion – pro-inflammatory and anti-inflammatory- suggesting that IL-17A may also contribute to terminate inflammation. Further, a reciprocal regulation of Th17 and regulatory T cells including the role of retinoic acid and TGF- is discussed. The discovery that patients with rheumatoid arthritis, allergic disorders, psor- sis and inflammatory bowel disease express IL-17A generated interest in the medical community and instigated a flurry of experimental research on the potential role of Th17 in inflammatory diseases. Experimental studies confirmed that IL-17A is induced and is critical for the development of allergic lung inflammation, arthritis, bacterial sepsis, experimental allergic encephalomyelitis and myocarditis, as well as other inflammatory con- tions including organ transplantation. The role of IL-17F and IL-22 is still poorly defined and is only slowly emerging.

Author: Marc A. Williams
Publisher: Elsevier
ISBN: 1908818069
Category : Medical
Languages : en
Pages : 315

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Allergens and respiratory pollutants is a collection of 12 authoritative papers that draws upon the collective expertise of world leaders in the fields of innate immunity, immunotoxicology and pulmonary biology. The book critically explores the biological and immunological mechanisms that contribute to immune dysfunction on exposure to allergens and the susceptibility to infectious disease on exposure to ambient pollutants. The clinical relevance of exposure to ambient airborne xenobiotics is critically discussed and collectively, this book provides an educational forum that links the health effects of environmental exposures, immune dysfunction and inflammatory airways disease. - Discusses recent advances in our understanding of cell-mediated innate immune mechanisms that occur during allergic inflammation and provides important timely coverage of diseases of concern and how such diseases are influenced by a dysfunctional immune system - Provides useful information on linking environmental 'danger signals' that provoke immune dysfunction and exacerbation of existing disease - Draws upon the collective expertise of an international college of leaders in the field, but also provides chapters that provide essential reference material

Author: Sharlene Velichko
Publisher:
ISBN: 9781124908731
Category :
Languages : en
Pages :

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The role of the proinflammatory cytokine interleukin-17 (IL-17) in the airway has been under investigation for the last 12 years. Many studies have been published demonstrating its pleiotropic role in the production of chemokines, cytokines, mucins, and antimicrobial proteins. Many in vivo models have demonstrated the association of IL-17 in airway inflammation in response to allergens as well as environmental insults, as well as chronic inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease and asthma. However, relatively little is known regarding the downstream signaling mechanisms by which IL-17 mediates its many effects. What is known is that the signaling is complex; IL-17 has been shown to involve multiple signaling pathways, including: the canonical NF-kappaB pathway, multiple mitogen-activated protein (MAP) kinase pathways, as well as C/EBP, PI-3 kinase and JAK. Both cell type and target gene appear to determine the signaling pathway involved downstream of IL-17. Little is known regarding the protein-protein interactions that mediate these signaling events. What is known is that the intracellular protein Act1 (also known as CIKS) is an important downstream mediator of IL-17 induced signaling. Cells derived from Act1-deficient mice are largely unresponsive to IL-17A stimulation. Act1 has been shown to contain both TRAF6 and IL-17 receptor binding sites, and therefore acts as an intermediate to connect the activated IL-17 receptor complex to pathways downstream of TRAF6. However, Act1 has additional functions as well. It can also bind to the IL-25, CD40 and BAFF-R receptors, and has recently been shown to act as a U-box type E3 ubiquitin ligase. Recently, a single nucleotide polymorphism (SNP) that encodes a loss-of-function mutation in the gene for Act1, TRAF3IP2, was associated with psoriasis, an autoimmune inflammatory skin disease, and psoriatic arthritis. As IL-17 is associated with the pathogenesis of psoriasis, this is counter-intuitive to the known functions of Act1, indicating that Act1 may have other functions as well. This dissertation details a novel nuclear function for Act1 as a transcriptional enhancer. Subsequent RNA-seq comparison of cells ectopically expressing Act1 and IL-17A stimulated cells identified a number of cornified envelope constituents whose expression is up-regulated by both Act1 and IL-17. The cornified envelope is a structure formed in the outermost layer of stratified squamous epithelia. Finally, we detail the use of a yeast two hybrid assay to identify novel Act1 interacting proteins, and further characterize the interaction of Act1 with one of these proteins, COMMD1 (copper metabolism (Murr1) domain containing 1), which might represent a new target of Act1's ubiquitin ligase activity.

Author: Paige Lacy
Publisher: Frontiers Media SA
ISBN: 2889195503
Category : Immunologic diseases. Allergy
Languages : en
Pages : 135

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The release of cytokines, chemokines, and other immune-modulating mediators released from innate immune cells, including eosinophils, neutrophils, macrophages, dendritic cells, mast cells, and epithelial cells, is an important event in immunity. Cytokine synthesis and transportation occurs through the canonical protein trafficking pathway associated with endoplasmic reticulum and Golgi. How cytokines are released upon their exit from the trans-Golgi network varies enormously between cell types, and in many cells this has not yet been characterized. This issue delves into the plethora of cytokines released by innate immune cells, and where possible, shines light on specific mechanisms that regulate trafficking and release of Golgi-derived vesicles. Each cell type also shows varying degrees of dependency on microtubule organization and actin cytoskeleton remodeling for cytokine secretion. Understanding the mechanisms of cytokine secretion will reveal the inner workings of individual innate immune cell types, and allow identification of critical regulatory steps in cytokine release.

Author: Li-Yin Hung
Publisher:
ISBN:
Category :
Languages : en
Pages :

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Results from recent studies suggest that in addition to the barrier function, airway epithelial cells (AECs) also actively participating in airway immune response. We previously demonstrated that IL-17A is a potent inducer of human [beta]-defensin (hBD) 2 and CCL20 expression in well-differentiated human AECs. In addition to the anti-microbial activity, both hBD2 and CCL20 are principal chemotactic ligands of CCR6, which is expressed by dendritic cells (DC) and T lymphocytes. To further explore the chemotactic significance of IL-17A in the mouse system, we conducted studies using primary mouse AECs and Cc10-Il17 transgenic animals, which display airway overexpression of IL-17A. We found that mouse AECs expressed elevated mCcl20 in response to mIL-17A in an NF-[kappa]B-dependent manner. Conditioned media from mIL-17A-treated mouse AECs stimulated the migration of CCR6-positive bone marrow-derived DC in vitro; this chemotactic activity was blocked by an anti-CCL20 neutralizing antibody. In Cc10-Il17 transgenic mice, we detected elevated mCcl20 in the lung and an increased number of CCR6-positive DCs in bronchoalveolar lavage fluid. These mice also display increased mucin production in their lungs compared to wild-type mice. Blocking the migration of CCR6-expressing cells in vivo by anti-CCR6 or anti-CCL20 antibody lowered mucin production in the airways, suggesting a functional role of IL-17A/CCL20 in regulating CCR6-positive DC migration and mucous cell metaplasia. IL-17A also induces the expression of IL-19, a proinflammatory cytokine in the IL-10 cytokine family, in human AECs. We have shown the association of IL-19 with asthma and that AECs were one of the potential sources of IL-19 in the disease. Using well-differentiated primary mouse AECs grown under air-liquid interface conditions, we demonstrated that Th2 cytokines such as IL-4 and IL-13 could induce Il19 expression. In the OVA mouse asthma model, Il19 expression was elevated in asthmatic lung tissue at the early stage. This elevation was observed in airway epithelial cells but not alveolar macrophages. An increase was only observed for IL-19 and not other IL-20 subfamily members, such as IL-20, IL-22, and IL-24. We further demonstrated that IL-19 could stimulate in vitro Th2 cell lineage differentiation of naïve T cells when added initially to the polarizing medium. These results demonstrate that IL-19 produced by airway epithelial cells at the early stage of the asthmatic response may further amplify the Th2 response through promoting T helper cell differentiation. IL-19 has also been shown to stimulate [beta]-defensin in keratinocytes, but its potential to induce defensin expression in the airways has not been characterized. Here we report that IL-19 is able to induce hBD gene (DEFB4) expression in human airway epithelial cell line HBE-1, as well as primary mouse airway cells. Both STAT1 and STAT3 are required in IL-19-induced DEFB4 although only STAT3 is significantly activated by IL-19 while STAT1 is constantly phosphorylated. STAT5 is also phosphorylated in HBE-1 but does not involve in DEFB4 induction; however knocking down STAT5 appears to alter basal DEFB4 level. In addition to IL-19 we also found other IL-20 subfamily cytokines, including IL-20, -22, -24, and -26, capable of stimulating DEFB4 expression in HBE-1 cells.

Author: Shadi Swaidani
Publisher:
ISBN:
Category : Asthma
Languages : en
Pages : 143

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Allergic asthma is a chronic inflammatory disorder of the lung and is characterized by dyspnea, wheezing, and cough due to episodes of bronchial inflammation and bronchoconstriction/airway hyperressponsiveness (AHR). Pathologically, asthma is manifested by an infiltration of CD4+ cells, neutrophils, eosinophils and mast cells, as well as smooth muscle and goblet cells hyperplasia, often associated with elevated serum IgE concentrations. The sensitization and progression towards allergic asthma are a result of reactivity of the airway epithelial cells and innate immune cells to allergens, and the subsequent induction of adaptive immunity. Antigen-induced allergic airway inflammation is mediated by CD4+ Th2 cells and their cytokines (IL-4, IL-5, IL-9 and IL-13). Recent studies have shown that IL-25 (also known as IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of Th2 responses. IL-25 is produced by airway epithelial cells, T lymphocytes of the CD4+ subset with a Th2 profile, and by innate effector eosinophils and basophils. However, the molecular mechanism for how IL-25 mediates Th2 immunity, remains elusive. We recently reported that Act1 is an essential signaling molecule for IL-25 receptor (IL-25R) signaling (Swaidani et al., 2009). We have also found that Act1 has E3 ubiquitin ligase activity and this function is critical for downstream signaling. Importantly, Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1 (CCL11), and pulmonary eosinophilia and resulted in diminished Th2 responses and less lung inflammation in a mouse model of allergic pulmonary inflammation. More specifically, Act1 deficiency in epithelial cells reduced both IL-25- induced eosinophilia, while Act1 deficiency in T cells resulted in diminished Th2 responses and less lung inflammation. Further, Act1 deficiency in the T cell compartment and not the epithelial compartment, resulted in an abrogation of allergic humoral and airway hyperresponsiveness (AHR). Based on these findings, we hypothesize that the IL-25 induced Act1-mediated signaling pathway plays an essential role in driving Th2 cell responses and allergic pulmonary inflammation through the differential impact on epithelial and T cell compartments.

Author: Steven L. Kunkel
Publisher: Marcel Dekker
ISBN:
Category : Medical
Languages : en
Pages : 592

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Book Description
A comprehensive text providing much of the currently available knowledge in the field of cytokines. There are four areas covered, including general overviews of each of the major cytokines, listings of the important interactions these cytokines have with inflammatory cells, discussions of current an

Author: Peter Howarth
Publisher: CRC Press
ISBN: 9780429132582
Category : MEDICAL
Languages : en
Pages : 328

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Book Description
This landmark volume discusses the characteristics and impact of the remodeling process on airway function and clinical disease expression within the airway in asthma, covering pharmacological therapies and possible future targets relevant to regulating the remodeling process. Emphasizes the importance of treating underlying airway inflammation and the relevance of structural alterations to the airway wall, including glandular increases, enhanced collagen deposition within the submucosa, increased vasculature, smooth hypertrophy, and hyperplasias! Tracing the development and maintenance of bronchial hyperresponsiveness, decline in lung function, and loss of reversibility evident in chronic asthma, Airway Remodelingdescribes the contribution of inflammatory cells in the development of airway structural changes examines how pharmaceutical agents act and whether existing treatments modify or prevent remodeling in chronically inflamed asthmatic airways considers whether neural pathways initiate as well as contribute to the airway inflammatory cascade that leads to remodeling reviews the action of cytokines and growth factors on ASM signaling outlines novel approaches to regulating smooth muscle growth clarifies whether permanent ventilatory incapacity in asthma is caused by the uncoupling of the airway and the role of the lung parenchyma details high-resolution computerized tomography scan to measure the internal size of the airway at baseline, during challenge, or after bronchodilatation and more!Improving lung function and quality of life by reducing the need for emergency care, hospital admissions, and systemic steroid administration, Airway Remodeling is a superb reference for pulmonologists and respiratory system specialists; physiologists; pneumologists; allergists; pharmacologists; molecular, cellular, and lung biologists; and graduate and medical school students in these disciplines.