Abstract
T cell-mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell-mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4(+) and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-gamma-deficient mice indicate that IFN-gamma not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6-deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A-mediated hepatitis by activation of CD4(+) and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-gamma signaling and induction of antiapoptotic protein Bcl-X(L). STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Concanavalin A / toxicity
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Hepatitis, Autoimmune / etiology
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Hepatitis, Autoimmune / immunology
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Hepatitis, Autoimmune / metabolism*
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Hepatitis, Autoimmune / pathology
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Humans
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interleukin-6 / deficiency
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Interleukin-6 / genetics
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Intracellular Signaling Peptides and Proteins*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Biological
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Proteins / genetics
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Proteins / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Repressor Proteins*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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T-Lymphocytes / immunology*
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Proteins
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RNA, Messenger
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Repressor Proteins
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SOCS1 protein, human
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SOCS3 protein, human
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Socs1 protein, mouse
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Socs3 protein, mouse
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Stat1 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Concanavalin A
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Interferon-gamma