Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT.
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-alpha, granulocyte colony-stimulating factor, IFN-beta, and other cytokines. We found that LPS directly activated Jak2 and Stat5, whereas SOCS-1 inhibited LPS-induced Jak2 and Stat5 activation. Furthermore, AG490, a Jak-specific inhibitor, and dominant negative Stat5 only reduced LPS-induced IL-6 production. Additionally, Stat5 interacted with p50, resulting in recruitment of Stat5 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.
Kimura
Akihiro
A
Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Department of Molecular Medicine, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan.
Naka
Tetsuji
T
Muta
Tatsushi
T
Takeuchi
Osamu
O
Akira
Shizuo
S
Kawase
Ichiro
I
Kishimoto
Tadamitsu
T
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis; D053614:Janus Kinase 2; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D051379:Mice; D008817:Mice, Mutant Strains; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
D002352:Carrier Proteins; D016207:Cytokines; D015850:Interleukin-6; D053614:Janus Kinase 2; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C491590:Socs1 protein, mouse; C507926:Jak2 protein, mouse