Tyrosine phosphatase SHP-1 in oxidative stress and development of allergic airway inflammation.
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.
Cho
You Sook
YS
Division of Allergy and Clinical Immunology, Johns Hopkins Asthma Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Oh
Sun Young
SY
Zhu
Zhou
Z
D000485:Allergens / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D054418:Chemokine CCL20 / Q000276:immunology; D018946:Chemokine CCL5 / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000502:physiology*; D010269:Paraquat / Q000494:pharmacology; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism
D000485:Allergens; C493447:CCL20 protein, mouse; C503460:Ccl5 protein, mouse; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D050800:STAT6 Transcription Factor; D016753:Interleukin-10; D006861:Hydrogen Peroxide; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D010269:Paraquat