TY - JOUR
T1 - Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling expression
AU - Takatori, Hiroaki
AU - Nakajima, Hiroshi
AU - Kagami, Shin Ichiro
AU - Hirose, Koichi
AU - Suto, Akira
AU - Suzuki, Kotaro
AU - Kubo, Masato
AU - Yoshimura, Akihiko
AU - Saito, Yasushi
AU - Iwamoto, Itsuo
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2005/4/1
Y1 - 2005/4/1
N2 - In previous studies, we have shown that Th2 cell differentiation is diminished but Th1 cell differentiation is increased in Stat5a-deficient (Stat5a-/-) CD4+ T cells. In the present study, we clarified the molecular mechanisms of Stat5a-mediated Th cell differentiation. We found that enhanced Th1 cell differentiation and the resultant IFN-γ production played a dominant inhibitory role in the down-regulation of IL-4-induced Th2 cell differentiation of Stat5a-/- CD4+ T cells. We also found that IL-12-induced Stat4 phosphorylation and Th1 cell differentiation were augmented in Stat5a-/- CB4+ T cells. Importantly, the expression of suppressor of cytokine signaling (SOCS)3, a potent inhibitor of IL-12-induced Stat4 activation, was decreased in Stat5a -/- CD4+ T cells. Moreover, a reporter assay showed that a constitutively active form of Stat5a but not Stat6 activated the SOCS3 promoter. Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4+ T cells. Finally, the retrovirus-mediated expression of SOCS3 restored the impaired Th cell differentiation of Stat5a-/- CD4+ T cells. These results suggest that Stat5a forces the Th1/Th2 balance toward a Th2-type by preventing IL-12-induced Th1 cell differentiation through the induction of SOCS3.
AB - In previous studies, we have shown that Th2 cell differentiation is diminished but Th1 cell differentiation is increased in Stat5a-deficient (Stat5a-/-) CD4+ T cells. In the present study, we clarified the molecular mechanisms of Stat5a-mediated Th cell differentiation. We found that enhanced Th1 cell differentiation and the resultant IFN-γ production played a dominant inhibitory role in the down-regulation of IL-4-induced Th2 cell differentiation of Stat5a-/- CD4+ T cells. We also found that IL-12-induced Stat4 phosphorylation and Th1 cell differentiation were augmented in Stat5a-/- CB4+ T cells. Importantly, the expression of suppressor of cytokine signaling (SOCS)3, a potent inhibitor of IL-12-induced Stat4 activation, was decreased in Stat5a -/- CD4+ T cells. Moreover, a reporter assay showed that a constitutively active form of Stat5a but not Stat6 activated the SOCS3 promoter. Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4+ T cells. Finally, the retrovirus-mediated expression of SOCS3 restored the impaired Th cell differentiation of Stat5a-/- CD4+ T cells. These results suggest that Stat5a forces the Th1/Th2 balance toward a Th2-type by preventing IL-12-induced Th1 cell differentiation through the induction of SOCS3.
UR - http://www.scopus.com/inward/record.url?scp=20144372087&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20144372087&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.174.7.4105
DO - 10.4049/jimmunol.174.7.4105
M3 - Article
C2 - 15778369
AN - SCOPUS:20144372087
VL - 174
SP - 4105
EP - 4112
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -