A regulatory role for suppressor of cytokine signaling-1 in T(h) polarization in vivo.
Suppressor of cytokine signaling (SOCS)-1 is an inhibitory molecule for JAK, and its deficiency in mice leads to lymphocyte-dependent multi-organ disease and perinatal death. Crossing of SOCS-1(-/-) mice on an IFN-gamma(-/-), STAT1(-/-) and STAT6(-/-) background revealed that the fatal disease of SOCS-1(-/-) mice is also dependent on IFN-gamma/STAT1 and IL-4/STAT6 signaling pathways. Since IFN-gamma and IL-4 are representative T(h)1 and T(h)2 cytokines respectively, here we investigated the role of SOCS-1 in T(h) differentiation. Freshly isolated SOCS-1(-/-) CD4(+) T cells stimulated with anti-CD3 rapidly produced larger amounts of IFN-gamma and IL-4 than control cells, suggesting that these mutant T cells had already differentiated into T(h)1 and T(h)2 cells in vivo. In addition, SOCS-1(+/-) CD4(+) T cells cultured in vitro produced significantly larger amounts of IFN-gamma and IL-4 than SOCS-1(+/+) cells. Similarly, SOCS-1(+/-) CD4(+) T cells produced more IFN-gamma and IL-4 than SOCS-1(+/+) cells after infection with Listeria monocytogenes and Nippostrongyrus braziliensis respectively. Since IL-12-induced STAT4 and IL-4-induced STAT6 activation is sustained in SOCS-1(-/-) T cells, the enhanced T(h) functions in SOCS-1(-/-) and SOCS-1(+/-) mice appear to be due to the enhanced effects of these cytokines. These results suggest that SOCS-1 plays a regulatory role in both T(h)1 and T(h)2 polarizations.
Fujimoto
Minoru
M
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
Tsutsui
Hiroko
H
Yumikura-Futatsugi
Shizue
S
Ueda
Haruyasu
H
Xingshou
Ouyang
O
Abe
Tatsuo
T
Kawase
Ichiro
I
Nakanishi
Kenji
K
Kishimoto
Tadamitsu
T
Naka
Tetsuji
T
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D013154:Spleen / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases