This research proposal is focused on delineating the mechanisms by which the interleukin-5 (IL-5) family of cytokines can regulate the function of the human eosinophil. The importance of this goal is emphasized by the observation that IL-5 family cytokines mediate the recruitment and activation of eosinophils that likely contributes to the pathophysiologic features of asthma. However, the pathways whereby IL-5 receptor signaling is coupled to the control of eosinophilic inflammation in asthma are not well understood. In this regard, we are now in the unique position of being able to rigorously dissect the role of specific IL-5 signaling events in the modulation of eosinophil biology using both human blood and airway eosinophils. In addition, we have three key capabilities that should permit us to obtain new insights regarding eosinophil biology and asthma, including: a) routine access to highly purified human blood and airway eosinophils, including eosinophils isolated from people with asthma, b) the identification of key signaling molecules involved in mediating IL-5 and chemokine action in peripheral and airway eosinophils, including members of the Ras G-protein superfamily, the MAP kinases (ERKs 1 and 2), and several STAT transcription factors, and c) the development of methods for the analysis of cytokine/chemokine signaling in human eosinophils, including a technique for the introduction of dominant-negative molecules into primary human eosinophils. These tools will be used to test the overall hypothesis that IL-5 receptor signaling and regulation of eosinophil function involves the action of low MW G-proteins of the Ras superfamily, ERKs 1 and 2, and several STAT factors, and that the role of these pathways is not only to mediate the direct effects of IL-5 related cytokines on eosinophil function, but that they are also critical for priming blood cells to become responsive to a variety of other factors involved in the control of this cell?s inflammatory capacity. Accordingly, the following lines of investigation are proposed: 1) Test the hypothesis that activation of Ras superfamily G-proteins is essential for IL-5 to enhance the inflammatory capacity of the human blood eosinophil. 2) Evaluate the mechanism whereby IL-5 primes human blood eosinophils to respond to chemokines and ascertain how the requirement for this priming processes is bypassed in airway cells. 3) Examine the role of STAT3- and STAT5-dependent pathways in IL-5-mediated regulation of human eosinophil gene expression and biological responsiveness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
2P50HL056396-06
Application #
6565042
Study Section
Project Start
2002-01-05
Project End
2006-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
6
Fiscal Year
2002
Total Cost
$196,240
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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