In the present paper, we clearly demonstrate that activation of STAT1 promotes, whereas activation of STAT3 protects against, Con A–induced liver injury. In addition to such functional antagonism, STAT1 and STAT3 also mutually inhibit one another, at least in hepatocytes, by the induction of SOCS. To date, eight SOCS proteins (SOCS1–SOCS7 and CIS) have been identified (20
). Among them, SOCS1 and SOCS3 appear to be the most potent inhibitors of cytokine signaling (49
). Here, we demonstrate that both SOCS1 and SOCS3 are markedly induced, whereas SOCS2 and CIS are only slightly enhanced in the liver of Con A–induced hepatitis, suggesting that SOCS1 and SOCS3 may be the most important suppressors of STAT1 and STAT3 signaling in this model. Several lines of evidence indi-cate that induction of SOCS1 in the liver is mainly controlled by STAT1 activation. First, disruption of the STAT1
gene in STAT1–/–
mice almost completely abolished Con A–mediated induction of SOCS1, although STAT3 activation was markedly enhanced and prolonged in these mice (Figure ). Second, IFN-γ–mediated induction of SOCS1 was completely abolished in primary STAT1–/–
mouse hepatocytes, whereas induction of SOCS3 was enhanced in these cells. Third, enhanced STAT1 activation correlated with prolonged induction of SOCS1 mRNA expression in IL-6–/–
mice (Figure ). Finally, STAT1 plays an essential role in induction of IRF-1 (Figures , , and ), a key transcription factor controlling SOCS1 gene transcription (50
). SOCS1 was originally identified in a functional screen for factors that inhibit IL-6 signaling (51
) and later identified as a general negative feedback inhibitor for cytokine signaling (21
). Thus, STAT1-mediated induction of SOCS1 not only is a negative feedback loop for STAT1 activation, but also attenuates activation of STAT3 in Con A–induced hepatitis.
SOCS3 was induced in Con A–mediated hepatitis, and such induction positively correlated with STAT3 activation (Figure d and Figure a). Elimination of the STAT1
gene did not reduce, but rather enhanced, SOCS3 induction (Figure d and Figure ). Collectively, these findings suggest that STAT3 plays a more important role than STAT1 in inducing SOCS3 in this model of hepatitis. Induction of SOCS3 controlled predominantly by STAT3 in the liver is also suggested in another model of liver regeneration (52
). In this model, SOCS3 but not SOCS1 is markedly induced, which correlates with activation of STAT3 but absent STAT1 activation (52
). SOCS3 has been shown to negatively regulate STAT1 and STAT3 activation by inhibition of JAKs (21
). Thus, it is very likely that induction of SOCS3 attenuates both STAT1 and STAT3 in Con A–induced hepatitis.
In summary, our findings suggest that T cell–induced hepatitis is tightly controlled by mutual functional antagonism of IFN-γ/STAT1 and IL-6/STAT3, which negatively regulate one another through the induction of SOCS. Elevation of IFN-γ and IL-6 is observed not only in this Con A–induced murine model of hepatitis, but also in a variety of human liver disorders, including viral hepatitis (7
), autoimmune hepatitis (6
), primary biliary cirrhosis (58
), and alcoholic liver disease (59
), suggesting that human liver disorders may also be controlled by mutual antagonism of IFN-γ/STAT1 and IL-6/STAT3. Modulation of such mutual antagonism between STAT1 and STAT3 could offer a novel approach in the treatment of T cell–mediated liver damage in human liver disease.