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(American Journal of Pathology. 2006;169:96-104.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051160

Overexpression of the Transcription Factor GATA-3 Enhances the Development of Pulmonary Fibrosis

Toru Kimura^*, Yukio Ishii^*, Keigyou Yoh, Yuko Morishima^*, Takashi Iizuka^*, Takumi Kiwamoto^*, Yosuke Matsuno^*, Shinsuke Homma^*, Akihiro Nomura^*, Tohru Sakamoto^*, Satoru Takahashi and Kiyohisa Sekizawa^*

From the Departments of Respiratory Medicine^* and Nephrology, Institute of Clinical Medicine, and the Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan

Recent studies have demonstrated that Th2 cytokines, such as interleukin-4 and interleukin-13, enhance fibrotic processes by activating fibroblast proliferation and collagen production, whereas interferon-, a Th1 cytokine, inhibits these processes. Th1 and Th2 cells both differentiate from common T precursor cells, with transcription factor GATA-3 a key regulator of Th2 differentiation. In the present study, therefore, we examined the effects of GATA-3 overexpression on the development of pulmonary fibrosis in a mouse model. Wild-type C57BL/6 mice and GATA-3-overexpressing (GATA-3-tg) mice of the same background were intratracheally treated with bleomycin. The survival rate after bleomycin was significantly decreased in GATA-3-tg mice compared with wild-type mice. The degree of pulmonary fibrosis was much greater in GATA-3-tg mice than in wild-type mice 28 days after bleomycin treatment. Lung interferon- concentration was significantly decreased in GATA-3-tg mice compared with wild-type mice by 7 days after either saline or bleomycin treatment. The concentration of transforming growth factor-ß, a fibrogenic cytokine, was significantly higher in GATA-3-tg mice than in wild-type mice. Exogenous administration of interferon- to GATA-3-tg mice improved the degree of pulmonary fibrosis and thus increased survival. These results indicate that overexpression of GATA-3 enhances the development of pulmonary fibrosis, possibly by reducing interferon- levels in the lung.

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