We have found that mice that are unable to generate Thi7 cells and mice that are unable to respond to IL- 17 (due to global loss of IL-17 receptor C) are protected from airway hyperresponisveness in two models of allergic asthma. We also found that IL-17A directly increases the contractility of both murine and human airway smooth muscle through a pathway we characterized involving activation of NF-kB, increased expression of RhoA and enhancement of myosin phosphorylation. In addition, we found dramatic synergy between IL-17 and the Th2 cytokine IL-13 in enhancing airway smooth muscle contraction. In the proposed studies we will first determine the relative contributions of direct effects of IL-17 on airway smooth muscle or adjacent airway epithelium in vivo utilizing mice that specifically lack IL-17RC or the key IL-17 receptor signaling molecule, Act-1, only in smooth, only in lung epithelial cells or in both cell types, and by analyzing effects on contraction of human bronchi with or without the overlying epithelium. Because synergistic interactions between IL-17 and IL-13 might have special relevance to therapeutic strategies in asthma, we will also carefully disect the site(s) of signal amplification that underlie the synergistic effects of these cytokines on human airway smooth muscle, including smooth muscle cells cultured from patients with asthma. Finally, we will utilize the 3 cohorts of patients with asthma to be analyzed in the Clinical Subject and Biospecimen Core to determine the relationships between the signaling responses in airway smooth muscle cells, the number and location of IL-13 and IL-17 producing cells and airway hyperresponsiveness in patients with moderate or severe asthma and in responses to segmental allergen challenge. These studies should complement the studies proposed in Project 1 to study effects of the same cytokines on airway epithelial cells and the studies proposed in Project 3 to examine the dynamics of IL-13 and IL-17 production and signaling in asthmatic airways. Together, the proposed studies should provide important details about how these critical cytokines contribute to the initiation and persistence of allergic asthma and should identify novel steps for intervention.
', IL-13 and IL-17 both play important roles in models of allergic asthma and both have been strongly implicated in asthma in humans. In this proposal we will study how these two cytokines work together on airway smooth muscle, the cell type responsible for the exaggerated airway narrowing that characterizes asthma.
|Bhakta, Nirav R; Christenson, Stephanie A; Nerella, Srilaxmi et al. (2018) IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma. Am J Respir Crit Care Med 197:313-324|
|Levin, Albert M; Gui, Hongsheng; Hernandez-Pacheco, Natalia et al. (2018) Integrative approach identifies corticosteroid response variant in diverse populations with asthma. J Allergy Clin Immunol :|
|Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386|
|Oh, Sam S; Du, Randal; Zeiger, Andrew M et al. (2017) Breastfeeding associated with higher lung function in African American youths with asthma. J Asthma 54:856-865|
|Sherenian, M G; Cho, S H; Levin, A et al. (2017) PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort. Clin Exp Allergy 47:1150-1158|
|Bonser, Luke R; Erle, David J (2017) Airway Mucus and Asthma: The Role of MUC5AC and MUC5B. J Clin Med 6:|
|Yi, L; Cheng, D; Zhang, K et al. (2017) Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis. Mucosal Immunol 10:1491-1503|
|Sundaram, Aparna; Chen, Chun; Khalifeh-Soltani, Amin et al. (2017) Targeting integrin ?5?1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest 127:365-374|
|Thakur, Neeta; Barcelo, Nicolas E; Borrell, Luisa N et al. (2017) Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies. Chest 151:804-812|
|McAleer, Jeremy P; Nguyen, Nikki L H; Chen, Kong et al. (2016) Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome. J Immunol 197:97-107|
Showing the most recent 10 out of 117 publications