Molecular regulation and effector functions of the high affinity IgE receptor (FcεRI) in human airway smooth muscle cells

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dc.contributor.authorRedhu, Naresh Singh
dc.contributor.examiningcommitteeHalayko, Andrew J. (Physiology) Uzonna, Jude E. (Immunology) Kung, Sam (Immunology) Vliagoftis, Harissios (University of Alberta)en_US
dc.contributor.supervisorSoussi Gounni, Abdelilah (Immunology)en_US
dc.date.accessioned2012-04-13T15:02:55Z
dc.date.available2012-04-13T15:02:55Z
dc.date.issued2012en_US
dc.date.issued2010en_US
dc.date.issued2011en_US
dc.date.issued2011en_US
dc.date.issued2011en_US
dc.date.issued2009en_US
dc.degree.disciplineImmunologyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractThe prevalence and economic burden of chronic airway disorders such as asthma is on the rise annually. Allergic asthma is characterized by chronic airway inflammation, airway hyper-responsiveness (AHR), and structural airway remodeling due to increased smooth muscle mass. Most allergic asthma occurs due to the overproduction of immunoglobulin E (IgE) antibodies against common allergens. Classically, IgE has been shown to modulate airway smooth muscle (ASM) contraction/relaxation which is believed to be the underlying cause of airway hyperreactivity. However, the molecular mechanisms underlying IgE effects on ASM cell are not established. Recently, the high-affinity Fc receptor for IgE (FcεRI) has been identified in human ASM cells in vitro and in vivo within bronchial biopsies of allergic asthma patients. However, it is unknown whether FcεRI activation on ASM can modulate the immune response within the airways. We hypothesized that the IgE-FcεRI interaction plays a key role in inducing phenotypic and functional changes in ASM cells that eventually contributes to the establishment of airway inflammation, AHR, and remodeling. We sought to investigate the regulation, effector functions, and underlying mechanisms of FcεRI activation in ASM cells. Our work shows that the proinflammatory tumor necrosis factor (TNF) and T helper type 2 (Th2) cytokine interleukin (IL)-4 enhanced the FcεRI abundance and amplified the IgE-induced chemokine (eotaxin-1/CCL11, RANTES/CCL5, IL-8/CXCL8, and IP-10/CXCL10) release in ASM cells via transcriptional mechanisms. Both TNF and IgE induced a novel, Th2-favoring cytokine thymic stromal lymphopoietin (TSLP) through the activation of spleen tyrosine kinase (Syk), and nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). In addition, IgE induced de novo DNA synthesis and ASM cell proliferation via mitogen-activated protein kinases (MAPKs) and signal-transducer and activator of transcription 3 (STAT3) activation. Collectively, our data suggest that the IgE-induced FcεRI activation leads to the expression of multiple chemokines in ASM which may indirectly recruit inflammatory cells and promote allergic airway inflammation; IgE induces TSLP which can promote the Th2 immune responses within the airways; and IgE may potentially induce airway remodeling by directly inducing ASM cell proliferation. Therefore, targeting the IgE-FcεRI network on ASM may offer a novel therapeutic strategy in allergic asthma.en_US
dc.description.noteMay 2012en_US
dc.identifier.citationRedhu NS, Saleh Ali, Shan L, Gerthoffer WT, Halayko AJ, Lamkhioued B, Gounni AS. Pro-inflammatory and Th-2 Cytokines Regulate the High Affinity IgE Receptor (FcRI) Expression and IgE-dependant Activation of Human Airway Smooth Muscle Cells. PLoS One. 2009 Jul 7;4(7):e6153.en_US
dc.identifier.citationShan L, Redhu NS, Saleh A, Halayko AJ, Chakir J, Gounni AS. Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways. J Immunol. 2010 Jun 15;184(12):7134-43. Epub 2010 May 14.en_US
dc.identifier.citationRedhu NS, Saleh A, Halayko AJ, Ali AS, Gounni AS. Essential role of NF-κB and AP-1 transcription factors in TNF-α-induced TSLP expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2011 Mar;300(3):L479-85. Epub 2010 Dec 10.en_US
dc.identifier.citationRedhu NS, Saleh A, Lee HC, Halayko AJ, Ziegler SF, Gounni AS. IgE induces transcriptional regulation of thymic stromal lymphopoietin in human airway smooth muscle cells. J Allergy Clin Immunol. 2011 Oct;128(4):892-896.e2. Epub 2011 Aug 11.en_US
dc.identifier.citationRedhu NS, Gounni AS. Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clin Exp Allergy. 2011 Dec 14. doi: 10.1111/j.1365-2222.2011.03919.x. [Epub ahead of print]en_US
dc.identifier.citationRedhu NS, Shan L, Gounni AS. Fc{varepsilon} Receptor Expression in Human Airway Smooth Muscle Cells. Am J Respir Cell Mol Biol. 2012 Apr;46(4):559-60.en_US
dc.identifier.urihttp://hdl.handle.net/1993/5305
dc.language.isoengen_US
dc.publisherPLoS One (The Public Library of Science, USA)en_US
dc.publisherJ Immunol (The American Association of Immunologists, Inc., USA)en_US
dc.publisherAm J Physiol Lung Cell Mol Physiol (The American Physiological Society, USA)en_US
dc.publisherJ Allergy Clin Immunol (The Elsevier Inc., USA)en_US
dc.publisherClin Exp Allergy (The John Wiley & Sons, Inc.)en_US
dc.publisherAm J Respir Cell Mol Biol (The American Thoracic Society, USA)en_US
dc.rightsopen accessen_US
dc.subjectasthmaen_US
dc.subjectairway smooth muscleen_US
dc.subjectIgEen_US
dc.subjectFc receptoren_US
dc.subjectTSLPen_US
dc.subjectinflammationen_US
dc.titleMolecular regulation and effector functions of the high affinity IgE receptor (FcεRI) in human airway smooth muscle cellsen_US
dc.typedoctoral thesisen_US
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