Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression.
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-gamma 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(-/-) CD4(+) 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.
Takatori
Hiroaki
H
Department of Allergy and Clinical Immunology, Chiba University School of Medicine, Chiba City, Japan.
Nakajima
Hiroshi
H
Kagami
Shin-ichiro
S
Hirose
Koichi
K
Suto
Akira
A
Suzuki
Kotaro
K
Kubo
Masato
M
Yoshimura
Akihiko
A
Saito
Yasushi
Y
Iwamoto
Itsuo
I
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008894:Milk Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; D013154:Spleen / Q000166:cytology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D012097:Repressor Proteins; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; C494091:Stat4 protein, mouse; C494093:Stat5a protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma