A Critical role of SHP-1 in regulation of type 2 inflammation in the lung

Sun Young Oh, Tao Zheng, Yoon Keun Kim, Lauren Cohn, Robert J. Homer, Andrew N.J. McKenzie, Zhou Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

Asthma is a chronic inflammatory disorder of the airways. Type 2 T helper (Th) cell-dominated inflammation in the lung is a hallmark of asthma. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is a negative regulator in the signaling pathways of many growth factor and cytokine receptors. However, a direct role of SHP-1 in the IL-4/IL-13 signaling pathway has not been established. In this study,we sought to define the function of SHP-1 in the lung by characterizing the pulmonary inflammation of viable motheaten (mev) mice, and to investigate the molecular mechanisms involved. Pulmonary histology, physiology, and cytokine expression of mev mice were analyzed to define the nature of the inflammation, and the gene-deletion approach was used to identify critical molecules involved. In mev mice, we observed spontaneous Th2-like inflammatory responses in the lung, including eosinophilia, mucus metaplasia, airway epithelial hypertrophy, pulmonary fibrosis, and increased airway resistance and airway hyperresponsiveness. The pulmonary phenotype was accompanied by up-regulation of Th2 cytokines and chemokines. Selective deletion of IL-13 or signal transducer and activator of transcription 6, key genes in the Th2 signaling pathway, significantly reduced, but did not completely eliminate, the inflammation in the lung. These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis.

Original languageEnglish (US)
Pages (from-to)568-574
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume40
Issue number5
DOIs
StatePublished - May 1 2009

Keywords

  • Lung
  • Motheaten mouse
  • Protein tyrosine phosphatase
  • Src homology 2 domain-containing protein tyrosine phosphatase-1
  • Type 2 T helper cell inflammation

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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