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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Noel, Patricia
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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