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  • Title: Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis.
    Author: Matsuno Y, Ishii Y, Yoh K, Morishima Y, Haraguchi N, Kikuchi N, Iizuka T, Kiwamoto T, Homma S, Nomura A, Sakamoto T, Ohtsuka M, Hizawa N, Takahashi S.
    Journal: Am J Respir Crit Care Med; 2007 Nov 15; 176(10):1015-25. PubMed ID: 17717199.
    Abstract:
    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)-gamma 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-gamma 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-gamma enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-gamma 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-gamma level. CONCLUSIONS: These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.
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