TY - JOUR
T1 - Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT
AU - Kimura, Akihiro
AU - Naka, Tetsuji
AU - Muta, Tatsushi
AU - Takeuchi, Osamu
AU - Akira, Shizuo
AU - Kawase, Ichiro
AU - Kishimoto, Tadamitsu
PY - 2005/11/22
Y1 - 2005/11/22
N2 - Suppressor of cytokine signaling-1 (SOCS-1) is one of the negative-feedback regulators of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We previously showed that SOCS-1 participates in LPS signaling, but it is not entirely clear yet how SOCS-1 suppresses LPS signaling. In this study, we demonstrate that SOCS-1 selectively inhibits LPS-induced IL-6 production through regulation of JAK-STAT but not production of TNF-a, granulocyte colony-stimulating factor, IFN-β, and other cytokines. We found that LPS directly activated Jak2 and StatS, whereas SOCS-1 inhibited LPS-induced Jak2 and StatS activation. Further-more, AG490, a Jak-specific inhibitor, and dominant negative StatS only reduced LPS-induced IL-6 production. Additionally, StatS interacted with p50, resulting in recruitment of StatS to the IL-6 promoter together with p50 in response to LPS stimulation. These findings suggest that the JAK-STAT pathway participates in LPS-induced IL-6 production and that SOCS-1 suppresses LPS signaling by regulating JAK-STAT.
AB - Suppressor of cytokine signaling-1 (SOCS-1) is one of the negative-feedback regulators of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We previously showed that SOCS-1 participates in LPS signaling, but it is not entirely clear yet how SOCS-1 suppresses LPS signaling. In this study, we demonstrate that SOCS-1 selectively inhibits LPS-induced IL-6 production through regulation of JAK-STAT but not production of TNF-a, granulocyte colony-stimulating factor, IFN-β, and other cytokines. We found that LPS directly activated Jak2 and StatS, whereas SOCS-1 inhibited LPS-induced Jak2 and StatS activation. Further-more, AG490, a Jak-specific inhibitor, and dominant negative StatS only reduced LPS-induced IL-6 production. Additionally, StatS interacted with p50, resulting in recruitment of StatS to the IL-6 promoter together with p50 in response to LPS stimulation. These findings suggest that the JAK-STAT pathway participates in LPS-induced IL-6 production and that SOCS-1 suppresses LPS signaling by regulating JAK-STAT.
KW - Innate immunity
KW - Jak2
KW - Stat5
KW - Toll-like receptor signal
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U2 - 10.1073/pnas.0508517102
DO - 10.1073/pnas.0508517102
M3 - Article
C2 - 16287972
AN - SCOPUS:28044461950
SN - 0027-8424
VL - 102
SP - 17089
EP - 17094
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -