1. SOCS-1/SSI-1-Deficient NKT Cells Participate in Severe Hepatitis through Dysregulated Cross-Talk Inhibition of IFN-γ and IL-4 Signaling In Vivo
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Tetsuji Naka, Keishi Adachi, Tomohiro Yoshimoto, Yoshinori Kawazoe, Kenji Nakanishi, Minoru Fujimoto, Hidetsugu Kohzaki, Hiroko Tsutsui, Nakagawa, Masashi Narazaki, Tadamitsu Kishimoto, and Yoshiaki Morita
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medicine.medical_treatment ,Immunology ,Suppressor of Cytokine Signaling Proteins ,Thymus Gland ,Biology ,Suppressor of cytokine signalling ,Hepatitis ,Interferon-gamma ,Mice ,Suppressor of Cytokine Signaling 1 Protein ,medicine ,otorhinolaryngologic diseases ,Immunology and Allergy ,Animals ,SOCS3 ,STAT1 ,Interleukin 4 ,STAT6 ,Mice, Knockout ,Suppressor of cytokine signaling 1 ,Natural killer T cell ,DNA-Binding Proteins ,Killer Cells, Natural ,Mice, Inbred C57BL ,Repressor Proteins ,Infectious Diseases ,Cytokine ,STAT1 Transcription Factor ,Liver ,Cancer research ,biology.protein ,Trans-Activators ,Interleukin-4 ,sense organs ,Carrier Proteins ,STAT6 Transcription Factor ,Signal Transduction - Abstract
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.
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