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Tyrosine phosphatase SHP-1 in oxidative stress and development of allergic airway inflammation.

Abstract
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.
AuthorsYou Sook Cho, Sun Young Oh, Zhou Zhu
JournalAmerican journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 39 Issue 4 Pg. 412-9 (Oct 2008) ISSN: 1535-4989 [Electronic] United States
PMID18441283 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Allergens
  • CCL20 protein, mouse
  • Ccl5 protein, mouse
  • Chemokine CCL20
  • Chemokine CCL5
  • STAT6 Transcription Factor
  • Interleukin-10
  • Hydrogen Peroxide
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse
  • Paraquat
Topics
  • Allergens (immunology)
  • Animals
  • Bronchoalveolar Lavage Fluid (cytology)
  • Cell Line
  • Chemokine CCL20 (immunology)
  • Chemokine CCL5 (immunology)
  • Dendritic Cells (immunology, pathology)
  • Epithelial Cells (drug effects, 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, physiology)
  • Respiratory Hypersensitivity (immunology, metabolism)
  • Respiratory Mucosa (drug effects, metabolism)
  • STAT6 Transcription Factor (metabolism)

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