TY - JOUR
T1 - Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin
AU - Ichiyama, Kenji
AU - Sekiya, Takashi
AU - Inoue, Naoko
AU - Tamiya, Taiga
AU - Kashiwagi, Ikko
AU - Kimura, Akihiro
AU - Morita, Rimpei
AU - Muto, Go
AU - Shichita, Takashi
AU - Takahashi, Reiko
AU - Yoshimura, Akihiko
N1 - Funding Information:
We thank K. Yasutomo for providing the Eomes cDNA construct. We also thank M. Asakawa, K. Fukuse, and N. Shiino for technical assistance. This work was supported by special grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO), The Mitsubishi Pharma Research Foundation, Kanae Foundation for the Promotion of Medical Science, The Mochida Memorial Foundation, and the Takeda Science Foundation.
PY - 2011/5/27
Y1 - 2011/5/27
N2 - Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation.
AB - Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation.
UR - http://www.scopus.com/inward/record.url?scp=79956324792&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79956324792&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2011.02.021
DO - 10.1016/j.immuni.2011.02.021
M3 - Article
C2 - 21600798
AN - SCOPUS:79956324792
SN - 1074-7613
VL - 34
SP - 741
EP - 754
JO - Immunity
JF - Immunity
IS - 5
ER -
