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Overexpression of GATA-3 Protects against the Development of Hypersensitivity Pneumonitis

¹ Department of Respiratory Medicine, ² Department of Nephrology, Institute of Clinical Medicine, and ³ Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki, Japan

Correspondence and requests for reprints should be addressed to Yukio Ishii, M.D., Ph.D., Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan. E-mail: ishii-y{at}md.tsukuba.ac.jp

Rationale: Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP).

Objectives: We examined the effect of GATA-3 overexpression on the development of HP in mice.

Methods: Wild-type C57BL/6 mice and GATA-3–overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmer's lung.

Measurements and Main Results: Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN)- in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3–overexpressing mice. The induction of T-bet and IFN- genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3–overexpressing mice after antigen exposure. Supplementation with recombinant IFN- enhanced lung inflammatory responses in GATA-3–overexpressing mice to the level of wild-type mice. Because antigen-induced IFN- production predominantly occurred in CD4⁺ T cells, nude mice were transferred with CD4⁺ T cells from either wild-type or GATA-3–overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4⁺ T cells from GATA-3–overexpressing mice than in those with wild-type CD4⁺ T cells, with a reduction of lung IFN- level.

Conclusions: These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.

Key Words: transcription factors • T lymphocytes • inflammation • interferon-

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Hypersensitivity pneumonitis is mediated by a Th1 immune response. The GATA binding protein-3 (GATA-3) transcriptional factor participates in Th2 differentiation and may be involved in regulating the pathogenesis of hypersensitivity pneumonitis (HP). What This Study Adds to the Field Overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.

 

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