SHP-1 deficient mast cells are hyperresponsive to stimulation and critical in initiating allergic inflammation in the lung

Li Zhang, Sun Young Oh, Xinxing Wu, Min Hee Oh, Fan Wu, John Thomas Schroeder, Clifford M Takemoto, Tao Zheng, Zhou Zhu

Research output: Contribution to journalArticle

Abstract

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 KitW-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 H2O2, LPS, and FcεI cross-linking, involving c-Kit-dependent and -independent processes. The FcεRI 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 FcεRI stimulation. When backcrossed to the KitW-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.

Original languageEnglish (US)
Pages (from-to)1180-1190
Number of pages11
JournalJournal of Immunology
Volume184
Issue number3
DOIs
StatePublished - Feb 1 2010

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Mast Cells
Pneumonia
Cytokines
Interleukin-13
Phenotype
Lung
SH2 Domain-Containing Protein Tyrosine Phosphatases
Asthma
Bone Marrow
T-Lymphocytes
Th2 Cells
src Homology Domains
Phosphoric Monoester Hydrolases
Interleukin-4
Cell Differentiation
Cell Survival
Phosphorylation

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

SHP-1 deficient mast cells are hyperresponsive to stimulation and critical in initiating allergic inflammation in the lung. / Zhang, Li; Oh, Sun Young; Wu, Xinxing; Oh, Min Hee; Wu, Fan; Schroeder, John Thomas; Takemoto, Clifford M; Zheng, Tao; Zhu, Zhou.

In: Journal of Immunology, Vol. 184, No. 3, 01.02.2010, p. 1180-1190.

Research output: Contribution to journalArticle

Zhang, Li ; Oh, Sun Young ; Wu, Xinxing ; Oh, Min Hee ; Wu, Fan ; Schroeder, John Thomas ; Takemoto, Clifford M ; Zheng, Tao ; Zhu, Zhou. / SHP-1 deficient mast cells are hyperresponsive to stimulation and critical in initiating allergic inflammation in the lung. In: Journal of Immunology. 2010 ; Vol. 184, No. 3. pp. 1180-1190.
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abstract = "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 KitW-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 H2O2, LPS, and FcεI cross-linking, involving c-Kit-dependent and -independent processes. The FcεRI 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 FcεRI stimulation. When backcrossed to the KitW-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.",
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AU - Wu, Xinxing

AU - Oh, Min Hee

AU - Wu, Fan

AU - Schroeder, John Thomas

AU - Takemoto, Clifford M

AU - Zheng, Tao

AU - Zhu, Zhou

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AB - 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 KitW-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 H2O2, LPS, and FcεI cross-linking, involving c-Kit-dependent and -independent processes. The FcεRI 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 FcεRI stimulation. When backcrossed to the KitW-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.

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