SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-gamma and IL-4 signaling in vivo.
Suppressor of cytokine signaling-1 (SOCS-1), also known as STAT-induced STAT inhibitor-1 (SSI-1), is a negative feedback molecule for cytokine signaling, and its in vivo deletion induces fulminant hepatitis. However, elimination of the STAT1 or STAT6 gene or deletion of NKT cells substantially prevented severe hepatitis in SOCS-1-deficient mice, while administration of IFN-gamma and IL-4 accelerated its development. SOCS-1 deficiency not only sustained IFN-gamma/IL-4 signaling but also eliminated the cross-inhibitory action of IFN-gamma on IL-4 signaling. These results suggest that SOCS-1 deficiency-induced persistent activation of STAT1 and STAT6, which would be inhibited by SOCS-1 under normal conditions, may induce abnormal activation of NKT cells, thus leading to lethal pathological changes in SOCS-1-deficient mice.
Naka
T
T
Department of Molecular Medicine, Osaka Graduate School of Medicine, Suita City, Osaka, Japan. naka@imed3.med.osaka-u.ac.jp
Tsutsui
H
H
Fujimoto
M
M
Kawazoe
Y
Y
Kohzaki
H
H
Morita
Y
Y
Nakagawa
R
R
Narazaki
M
M
Adachi
K
K
Yoshimoto
T
T
Nakanishi
K
K
Kishimoto
T
T
D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007371:Interferon-gamma / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000293:injuries / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013950:Thymus Gland / Q000002:abnormalities / Q000473:pathology; D015534:Trans-Activators / Q000276:immunology
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma