Allergic inflammation and asthma are characterized by eosinophilia and the increased production of interleukin 5 (Il-5) in blood and affected tissues. Eosinophils can promote both bronchial smooth muscle contraction and increased permeability of bronchial mucosa. Eosinophil- derived mediators [e.g., granule proteins, reactive oxygen species and leukotriene C4 (LTC4)], can evoke hyper-responsiveness, epithelial damage, inflammation and bronchoconstriction. IL-5 is known to regulate eosinophil function, which can contribute to the pathogenesis of asthma. For example, IL-5 stimulation of blood eosinophils can produce several functional changes that mirror the phenotypic characteristics of the airway eosinophil, and these IL-5-induced changes include the priming LTC4 release, the increased membrane expression of CD11b/CD18, the enhance adherence to endothelial cells, and prolonged survival. Because little is known about IL-5 signal transduction in eosinophils, the present project is designed to explore the mechanisms by which Il-5 mediates alterations in eosinophil function, thereby increasing its inflammatory potential. This proposal will test a model of IL-5 intracellular signaling processes that is based on studies by us and others on the IL-5 family of cytokines. Our overall goal is to assess the importance of various aspects of this model to the intracellular events in human eosinophils stimulated with IL-5, and to relate these signaling processes to eosinophil function. The studies will focus on functional changes, namely chemotaxis, adherence to endothelium, LTC4 generation and suppression of apoptotic cell death, that are of particular relevance to the inflammatory capacity and accumulation of eosinophils in the pathogenesis of asthma. The proposed research centers around our observation that IL-5 stimulates the tyrosine phosphorylation of several cellular proteins, including the phosphorylation and activation of a 45-kDa mitogen- activated protein kinase (MAP kinase). The central hypothesis is developed that multiple pathways are involved in the IL-5 mediated tyrosine phosphorylation and activation of MAP kinases in eosinophils. To test this hypothesis, we will analyze the events that link IL-5 receptor activation to MAP kinase stimulation, such as pathways encompassing tyrosine kinases, Ras, protein kinase C, and/or pertussis toxin-sensitive G-proteins. Secondly, we will also examine selected processes that may result from IL-5-stimulated MAP kinase activity, including the regulation of phospholipase A2, ribosomal S6 kinase II (Rsk) and the hematopoietic transcription factor GATA-2, since these proteins are established MAP kinase substrates. These investigations lead to the related hypothesis that MAP kinase activation is a key intracellular mechanism, that along with other signaling events, is associated with IL-5 mediated changes in eosinophil function, including the priming of LTC4 generation, increased adherence to endothelial cells, chemotaxis and suppression of apoptotic cell death. In sum, it is anticipated that these studies will lead to a greater understanding of the molecular processes associated with eosinophilic inflammation that is a major characteristic of the pathophysiology of asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL056396-04
Application #
6302440
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$229,048
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kelly, Elizabeth A; Esnault, Stephane; Johnson, Sean H et al. (2016) Human eosinophil activin A synthesis and mRNA stabilization are induced by the combination of IL-3 plus TNF. Immunol Cell Biol 94:701-8
Lee, Yong Gyu; Jeong, Jong Jin; Nyenhuis, Sharmilee et al. (2015) Recruited alveolar macrophages, in response to airway epithelial-derived monocyte chemoattractant protein 1/CCl2, regulate airway inflammation and remodeling in allergic asthma. Am J Respir Cell Mol Biol 52:772-84
Park, Gye Young; Lee, Yong Gyu; Berdyshev, Evgeny et al. (2013) Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am J Respir Crit Care Med 188:928-40
Sorkness, Ronald L; Szakaly, Renee J; Rosenthal, Louis A et al. (2013) Viral bronchiolitis in young rats causes small airway lesions that correlate with reduced lung function. Am J Respir Cell Mol Biol 49:808-13
Denlinger, Loren C; Kelly, Elizabeth A B; Dodge, Ann M et al. (2013) Safety of and cellular response to segmental bronchoprovocation in allergic asthma. PLoS One 8:e51963
Gavala, M L; Kelly, E A B; Esnault, S et al. (2013) Segmental allergen challenge enhances chitinase activity and levels of CCL18 in mild atopic asthma. Clin Exp Allergy 43:187-97
Oh, Jiyoung; Malter, James S (2013) Pin1-FADD interactions regulate Fas-mediated apoptosis in activated eosinophils. J Immunol 190:4937-45
Ochkur, Sergei I; Kim, John Dongil; Protheroe, Cheryl A et al. (2012) A sensitive high throughput ELISA for human eosinophil peroxidase: a specific assay to quantify eosinophil degranulation from patient-derived sources. J Immunol Methods 384:10-20
Curran, Colleen S; Bertics, Paul J (2012) Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1? and MCP-1 in GM-CSF-treated human primary eosinophils. J Interferon Cytokine Res 32:450-61
Kelly, Elizabeth A B; Liu, Lin Ying; Esnault, Stephane et al. (2012) Potent synergistic effect of IL-3 and TNF on matrix metalloproteinase 9 generation by human eosinophils. Cytokine 58:199-206

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