Tyrosine Phosphatase SHP-1 in Oxidative Stress and Development of Allergic Airway Inflammation

• Published in: American journal of respiratory cell and molecular biology Vol. 39; no. 4; pp. 412 - 419
• Main Authors: Cho, You Sook, Oh, Sun Young, Zhu, Zhou
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01.10.2008; American Thoracic Society
• Subjects: Allergens - immunology; Animals; Bronchoalveolar Lavage Fluid - cytology; Cell Line; Chemokine CCL20 - immunology; Chemokine CCL5 - immunology; Dendritic Cells - immunology; Dendritic Cells - pathology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Humans; Hydrogen Peroxide - pharmacology; Inflammation - immunology; Interleukin-10 - biosynthesis; Mice; Mice, Mutant Strains; Oxidative Stress - physiology; Paraquat - pharmacology; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - physiology; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - metabolism; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; STAT6 Transcription Factor - metabolism
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2007-0229OC

Oxidative stress has been implicated in allergic responses. SHP-1 is a target of oxidants and has been reported as a negative regulator in a mouse model of asthma. We investigated the effect of oxidative stress on the development of allergic airway inflammation in heterozygous viable motheaten (mev/+) mice deficient of SHP-1. Wild-type (WT) and mev/+ mice were compared in this study. Human alveolar epithelial cells (A549) transfected with mutant SHP-1 gene were used to evaluate the role of SHP-1 in lung epithelial cells. Hydrogen peroxide (H(2)O(2)) and Paraquat were used in vitro and in vivo, respectively. We also investigated whether mev/+ mice can break immune tolerance when exposed to aeroallergen intranasally. Compared with WT mice, bronchoalveolar lavage (BAL) cells and splenocytes from mev/+ mice showed a different response to oxidant stress. This includes a significant enhancement of intracellular reactive oxygen species and STAT6 phosphorylation in vitro and increased CCL20, decreased IL-10, and increased number of dendritic cells in BAL fluid in vivo. Mutant SHP-1-transfected epithelial cells secreted higher levels of CCL20 and RANTES after exposure to oxidative stress. Furthermore, break of immune tolerance, as development of allergic airway inflammation, was observed in mev/+ mice after allergen exposure, which was suppressed by antioxidant N-acetylcystein. These data suggest that SHP-1 plays an important role in regulating oxidative stress. Thus, increased intracellular oxidative stress and lack of SHP-1 in the presence of T helper cell type 2-prone cellular activation may lead to the development of allergic airway inflammation.