Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis.
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-gamma, 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-gamma 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-beta, a fibrogenic cytokine, was significantly higher in GATA-3-tg mice than in wild-type mice. Exogenous administration of interferon-gamma 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-gamma levels in the lung.
Kimura
Toru
T
Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.
Ishii
Yukio
Y
Yoh
Keigyou
K
Morishima
Yuko
Y
Iizuka
Takashi
T
Kiwamoto
Takumi
T
Matsuno
Yosuke
Y
Homma
Shinsuke
S
Nomura
Akihiro
A
Sakamoto
Tohru
T
Takahashi
Satoru
S
Sekizawa
Kiyohisa
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D007371:Interferon-gamma