SHP-1 deficient mast cells are hyperresponsive to stimulation and critical in initiating allergic inflammation in the lung.
Phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1)-deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype. We examined SHP-1 regulation of mast cell differentiation, survival, and functional responses to stimulation using bone marrow-derived mast cells from viable motheaten (mev) mice. We assessed pulmonary phenotypical changes in mev mice on the mast cell-deficient Kit(W-Sh) genetic background. The results showed that SHP-1 deficiency led to increased differentiation and survival, but reduced proliferation, of mast cells. SHP-1-deficient mast cells produced and released increased amounts of mediators and Th2 cytokines IL-4 and -13 spontaneously and in response to H(2)O(2), LPS, and Fc epsilonI cross-linking, involving c-Kit-dependent and -independent processes. The Fc epsilonRI signaling led to binding of SHP-1 to linker for activation of T cells 2 and enhanced linker for activation of T cells 2 phosphorylation in mev bone marrow-derived mast cells. Furthermore, the number of mast cells in the lung tissue of mev mice was increased and mast cell production and release of Th2 cytokines were distinctly increased upon Fc epsilonRI stimulation. When backcrossed to the Kit(W-Sh) background, mev mice had markedly reduced pulmonary inflammation and Th2 cytokine production. These findings demonstrate that SHP-1 is a critical regulator of mast cell development and function and that SHP-1-deficient mast cells are able to produce increased Th2 cytokines and initiate allergic inflammatory responses in the lung.
Zhang
Li
L
Division of Allergy and Clinical Immunology, The Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.
Oh
Sun Young
SY
Wu
Xinxing
X
Oh
Min Hee
MH
Wu
Fan
F
Schroeder
John T
JT
Takemoto
Clifford M
CM
Zheng
Tao
T
Zhu
Zhou
Z
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency* / Q000235:genetics*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse