Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness.
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 T lymphocytes. To clarify the role of GATA-3-expressing T cells in the pathophysiology of bronchial asthma, we utilized transgenic (Tg) 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 noninvasive 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 with nontreated 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.
Yamashita
Naomi
N
Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi Nishitokyo-shi, Tokyo 202-8585, Japan. naoyama@musashino-u.ac.jp
Tashimo
Hiroyuki
H
Ishida
Hirofumi
H
Matsuo
Yukiko
Y
Tamauchi
Hidekazu
H
Terashima
Masazumi
M
Yoshiwara
Ikuo
I
Habu
Sonoko
S
Ohta
Ken
K
D000402:Airway Obstruction / Q000503:physiopathology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D017931:DNA Primers; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology*
D017931:DNA Primers; D050990:GATA3 Transcription Factor; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin; D001094:Arachidonate 5-Lipoxygenase