Asthma is a chronic inflammatory disorder of the airways and Th2 inflammation is a key feature of asthma. The Th2 cytokines interleukin-4 (IL-4) and IL-13 have a central role in the pathogenesis of asthma. Both IL-4 and IL-13 require IL-4 receptor a (IL-4Ra) for downstream signaling, including activation of STAT6 pathway and activation of IRS-PI3 kinase pathway. However, the mechanisms for negative regulation of IL-4 and IL-13 signaling are not well defined. Several lines of evidence have suggested a role of Src homology 2 domain tyrosine phosphatase 1 (SHP-1) in the regulation of Th2 responses. It has been shown that IL-4Ra can bind SHP-1. Mutations in human IL-4Ra have been found to be associated with atopy and may enhance IL-4 signaling by decreased binding of IL-4Ra to SHP-1. Reduced SHP-1 activity in mice may enhance Th2 response in an allergen-induced asthma model. Severe deficiency of SHP-1 in mice causes a lethal phenotype called """"""""motheaten"""""""" and """"""""viable motheaten"""""""". Spontaneous severe pulmonary inflammation is believed the cause of death of these mice. However, the true nature of this pulmonary disease has not been elucidated. We observed that the pulmonary abnormalities of the viable motheaten mice remarkably resemble the key features of Th2 inflammation of the lung, found in asthma model and in IL-13 transgenic mice. Our preliminary studies show that the pulmonary phenotype is largely Th2 cytokine- and Th2 signaling-dependent. We hypothesize that SHP-1 is an important negative regulator of Th2 signaling pathway and SHP-1 deficiency induces Th2 inflammation in the lung and Th2 cytokines and downstream genes are critical in the pathogenesis of this spontaneous disorder. Our long-term goals are to 1) define the role of Th2 cytokines and their signaling pathways in generating the motheaten phenotype; 2) define the role of SHP-1 and its pathway as a crucial mechanism in regulating Th2 inflammation; 3) explore the potential utilities of enhanced SHP-1 as a regulator for Th2 disorders. These studies will provide valuable insight into the functional role of SHP-1 in the lung and into the molecular mechanisms by which Th2 inflammation in diseases such as asthma may be modulated. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079349-01A2
Application #
7143577
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2006-07-21
Project End
2010-06-30
Budget Start
2006-07-21
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$408,750
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cho, Seok Hyun; Oh, Sun Young; Lane, Andrew P et al. (2014) Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways. PLoS One 9:e103685
Fang, Ping; Zhou, Li; Zhou, Yuqi et al. (2014) Immune modulatory effects of IL-22 on allergen-induced pulmonary inflammation. PLoS One 9:e107454
Zhou, Li; Oh, Sun Young; Zhou, Yuqi et al. (2013) SHP-1 regulation of mast cell function in allergic inflammation and anaphylaxis. PLoS One 8:e55763
Kim, Y-S; Choi, E-J; Lee, W-H et al. (2013) Extracellular vesicles, especially derived from Gram-negative bacteria, in indoor dust induce neutrophilic pulmonary inflammation associated with both Th1 and Th17 cell responses. Clin Exp Allergy 43:443-54
Oh, Min-Hee; Oh, Sun Young; Lu, Jingning et al. (2013) TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis. J Immunol 191:5371-82
Yu, Jinho; Oh, Min Hee; Park, Ju-Un et al. (2012) Epicutaneous exposure to staphylococcal superantigen enterotoxin B enhances allergic lung inflammation via an IL-17A dependent mechanism. PLoS One 7:e39032
Chen, An; Lee, Sang-Myeong; Gao, Beixue et al. (2011) c-Abl-mediated tyrosine phosphorylation of the T-bet DNA-binding domain regulates CD4+ T-cell differentiation and allergic lung inflammation. Mol Cell Biol 31:3445-56
Oh, Min-Hee; Oh, Sun Young; Yu, Jinho et al. (2011) IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin. J Immunol 186:7232-42
Zhu, Zhou; Oh, Min-Hee; Yu, Jinho et al. (2011) The Role of TSLP in IL-13-induced atopic march. Sci Rep 1:23
Oh, S Y; Park, J-U; Zheng, T et al. (2011) Cbl-b regulates airway mucosal tolerance to aeroallergen. Clin Exp Allergy 41:434-42

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