The Role of ACT1 IN IL-25 Dependent TH2 Responses and Allergic Airway Inflammation and Airway Hyperresponsiveness PDF Download

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

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Book Description
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.