Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis.
BACKGROUND
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).


OBJECTIVE
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.


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.
Matsuno
Yosuke
Y
Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Ishii
Yukio
Y
Yoh
Keigyou
K
Morishima
Yuko
Y
Haraguchi
Norihiro
N
Kikuchi
Norihiro
N
Iizuka
Takashi
T
Kiwamoto
Takumi
T
Homma
Shinsuke
S
Nomura
Akihiro
A
Sakamoto
Tohru
T
Ohtsuka
Morio
M
Hizawa
Nobuyuki
N
Takahashi
Satoru
S
D000542:Alveolitis, Extrinsic Allergic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D016930:Saccharopolyspora; D020825:T-Box Domain Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098815:T-bet Transcription Factor
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007378:Interleukins; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma