title: 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.
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins Asthma Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: You Sook
authors.initials: YS
authors.lastname: Cho
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Oh
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
mesh_terms: 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
chemical_list: 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