T cell treatment with small interfering RNA for suppressor of cytokine signaling 3 modulates allergic airway responses in a murine model of asthma.
CD4(+) T cells, particularly T helper (Th) 2 cells, play a pivotal role in the pathophysiology of allergic asthma. Suppressor of cytokine signaling (SOCS) proteins control the balance of CD4(+) T cell differentiation. Mice that lack SOCS3 in T cells by crossing SOCS3-floxed mice with Lck-Cre-transgenic mice have reduced allergen-induced eosinophilia in the airways. Here, we studied the effects of SOCS3 silencing with small interfering (si) RNA in primary CD4(+) T cells on Th2 cell differentiation and on asthmatic responses in mice. Th2 cells were generated from ovalbumin (OVA)-specific T cell receptor-transgenic mice in vitro and transferred into recipient mice. Transfection of SOCS3-specific siRNA attenuated Th2 response in vitro. Adoptive transfer of SOCS3-siRNA T cells exhibited markedly suppressed airway hyperresponsiveness and eosinophilia after OVA challenge, with a concomitant decrease in OVA-specific CD4(+) T cell accumulation in the airways. To investigate the mechanism of this impaired CD4(+) T cell accumulation, we inactivated SOCS3 of T cells by crossing SOCS3-floxed (SOCS3(flox/flox)) mice with CD4-Cre transgenic mice. CD4-Cre × SOCS3(flox/flox) mice exhibited fewer IL-4-producing cells and more reduced eosinophil infiltration in bronchoalveolar lavage fluids than control mice in a model of OVA-induced asthma. Expression of CCR3 and CCR4 in CD4(+) T cells was decreased in CD4-Cre × SOCS3(flox/flox) mice. CCR4 expression was also decreased in CD4(+) T cells after transfer of SOCS3 siRNA-treated T cells. These findings suggest that the therapeutic modulation of SOCS3 expression in CD4(+) T cells might be effective in preventing the development of allergic asthma.
Moriwaki
Atsushi
A
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Inoue
Hiromasa
H
Nakano
Takako
T
Matsunaga
Yuko
Y
Matsuno
Yukiko
Y
Matsumoto
Takafumi
T
Fukuyama
Satoru
S
Kan-O
Keiko
K
Matsumoto
Koichiro
K
Tsuda-Eguchi
Miyuki
M
Nagakubo
Daisuke
D
Yoshie
Osamu
O
Yoshimura
Akihiko
A
Kubo
Masato
M
Nakanishi
Yoichi
Y
D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D015536:Down-Regulation; D006579:Heterozygote; D008212:Lymphocyte Depletion; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism*; D054397:Receptors, CCR3 / Q000378:metabolism; D054398:Receptors, CCR4 / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
C515351:Ccr3 protein, mouse; C515355:Ccr4 protein, mouse; D034741:RNA, Small Interfering; D054397:Receptors, CCR3; D054398:Receptors, CCR4; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins