Submitted on April 28, 2005
Accepted on December 19, 2005
Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness
Naomi Yamashita1*, Hiroyuki Tashimo2, Hirofumi Ishida2, Yukiko Matsuo1, Hidekazu Tamauchi3, Masazumi Terashima4, Ikuo Yoshiwara2, Sonoko Habu5, and Ken Ohta2
1 Department of Medicine, Teikyo University Scholol of Medicine, Tokyo, Japan; Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan
2 Department of Medicine, Teikyo University Scholol of Medicine, Tokyo, Japan
3 Department of Microbiology, Kitazato University School of Medicine, Kanagawa, Japan
4 Discovery Research Laboratories II, Sumitomo Pharmaceuticals. Co., Ltd., Osaka, Japan
5 Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
* To whom correspondence should be addressed. E-mail: naoyama{at}musashino-u.ac.jp.
The pathophysiological characteristics of bronchial asthma consist of chronic inflammation of airways, airway hyperresponsiveness, and bronchoconstriction. Studies have shown that T helper type 2 (Th2) cytokines produced by both T cells and mast cells in the airway contribute substantially to the initiation of inflammation in both experimental and human bronchial asthma. GATA-3 is a transcription factor essential to the production of Th2
cytokines by Th2 helper T lymphocytes. To clarify the role of GATA-3 expressing T cells in the pathophysiology of bronchial asthma, we utilized transgenic mice carrying the
GATA-3 gene and the ovalbumin (OVA)-specific T cell receptor gene (GATA-3-Tg/OVA-Tg). Mice were intranasally administrated OVA without systemic immunization.
Airway responses were analyzed with non-invasive and invasive whole body plethysmographs. GATA-3-Tg/ OVA-Tg mice exhibited significantly higher IL-13 and IL-4 protein expression in the airway. Although there were no differences in the types of infiltrating cells between GATA-3-Tg/ OVA-Tg and GATA-3-non Tg/ OVA-Tg mice and
no significant increase in IgE level in either group compared to non-treated mice, the response after ACh inhalation was significantly elevated in GATA-3-Tg/ OVA-Tg on the seventh day of intranasal treatment with OVA. This hyperresponsiveness was inhibited by 5-lipoxygenase inhibitor and IL-13 neutralization, suggesting that airway responses were induced through IL-13 and leukotriene pathway. In conclusion, airway hyperresponsiveness, a characteristic of bronchial asthma, is regulated at the level of GATA-3 transcription by T lymphocytes in vivo.
