TY - JOUR
T1 - Src homology 2 domain-containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung
AU - Oh, Sun Young
AU - Zheng, Tao
AU - Bailey, Monica L.
AU - Barber, Dwayne L.
AU - Schroeder, John T.
AU - Kim, Yoon Keun
AU - Zhu, Zhou
N1 - Funding Information:
Supported by National Institutes of Health (NIH) grant RO1HL074095 and an American Lung Association Research Grant to Z.Z. and NIH Grant KO8 to T.Z. D.L.B. is a National Cancer Institute of Canada Research Scientist supported by the National Cancer Institute of Canada and the Canadian Institutes of Health Research.
PY - 2007/1
Y1 - 2007/1
N2 - Background: Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the TH2 activation pathway has not been established. SHIP-1-/- mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis. Objective: To test our hypothesis, we characterized the pulmonary phenotype of SHIP-1-/- mice. Results: Analyses of lung histopathology and bronchoalveolar lavage cellularity revealed that the majority of SHIP-1-/- mice had progressive and severe pulmonary inflammation of macrophages, lymphocytes, neutrophils, and eosinophils; mucous hyperplasia; airway epithelial hypertrophy; and subepithelial fibrosis. These pathologic changes were accompanied by exaggerated production of TH2 cytokines and chemokines, including IL-4, IL-13, eotaxin, and monocyte chemoattractant protein 1, in the lung. Furthermore, the number of mast cells significantly increased, and many of these cells were undergoing degranulation, which was correlated with increased content and spontaneous release of histamine in the lung tissue of SHIP-1-/- mice. Conclusion: These findings provide strong evidence that mice lacking SHIP-1 have an allergic inflammation in the lung, suggesting that SHIP-1 plays an important role in regulating the TH2 signaling pathway and in maintaining lung homeostasis. Clinical implications: SHIP-1 as a regulator might be a potential therapeutic target for controlling allergic inflammation in diseases such as asthma.
AB - Background: Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the TH2 activation pathway has not been established. SHIP-1-/- mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis. Objective: To test our hypothesis, we characterized the pulmonary phenotype of SHIP-1-/- mice. Results: Analyses of lung histopathology and bronchoalveolar lavage cellularity revealed that the majority of SHIP-1-/- mice had progressive and severe pulmonary inflammation of macrophages, lymphocytes, neutrophils, and eosinophils; mucous hyperplasia; airway epithelial hypertrophy; and subepithelial fibrosis. These pathologic changes were accompanied by exaggerated production of TH2 cytokines and chemokines, including IL-4, IL-13, eotaxin, and monocyte chemoattractant protein 1, in the lung. Furthermore, the number of mast cells significantly increased, and many of these cells were undergoing degranulation, which was correlated with increased content and spontaneous release of histamine in the lung tissue of SHIP-1-/- mice. Conclusion: These findings provide strong evidence that mice lacking SHIP-1 have an allergic inflammation in the lung, suggesting that SHIP-1 plays an important role in regulating the TH2 signaling pathway and in maintaining lung homeostasis. Clinical implications: SHIP-1 as a regulator might be a potential therapeutic target for controlling allergic inflammation in diseases such as asthma.
KW - Phosphatase
KW - T2 inflammation
KW - allergy
KW - asthma
KW - phosphoinositide 3-kinase
KW - signaling
UR - http://www.scopus.com/inward/record.url?scp=33845932895&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845932895&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2006.08.029
DO - 10.1016/j.jaci.2006.08.029
M3 - Article
C2 - 17208593
AN - SCOPUS:33845932895
SN - 0091-6749
VL - 119
SP - 123
EP - 131
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -