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THE ROLE OF ACT1 IN IL-25 DEPENDENT TH2 RESPONSES AND ALLERGIC AIRWAY INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS

Swaidani, Shadi
http://rave.ohiolink.edu/etdc/view?acc_num=case1270240862

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
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.
Xiaoxia Li, PhD (Advisor)
David Kaplan, MD, PhD (Committee Chair)
Mark Aronica, MD (Advisor)
Serpil Erzurum, MD (Committee Member)
Tom Hamilton, PhD (Committee Member)
Tom McIntyre, PhD (Committee Member)
Immunology
act1; IL-25; Asthma

Recommended Citations

Citations

  • Swaidani, S. (2010). THE ROLE OF ACT1 IN IL-25 DEPENDENT TH2 RESPONSES AND ALLERGIC AIRWAY INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1270240862

    APA Style (7th edition)

  • Swaidani, Shadi. THE ROLE OF ACT1 IN IL-25 DEPENDENT TH2 RESPONSES AND ALLERGIC AIRWAY INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1270240862.

    MLA Style (8th edition)

  • Swaidani, Shadi. "THE ROLE OF ACT1 IN IL-25 DEPENDENT TH2 RESPONSES AND ALLERGIC AIRWAY INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270240862

    Chicago Manual of Style (17th edition)

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© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.