Abstract
Autoimmune hepatitis is a condition where immune cells target and destroy liver cells. To date, molecular mechanisms of inflammation mediated fibrosis and necrotic changes in liver cells are poorly understood. STAT4 is expressed in immune cells as well structural cells such as hepatocytes. However, the role of STAT4 in autoimmune hepatitis is ill-defined. Therefore, we investigated the role of STAT4 signaling in Concanavalin A (ConA)-induced auto-immune hepatitis model. Our data indicate STAT4 -/- mice but not WT, IL-12p35 -/- or IL-12p40 -/- mice were resistant to ConA-induced hepatitis as measured by liver pathology and the serum alanine aminotransferase (ALT) level. Histopathological analysis of liver sections showed significant necrotic lesion in WT, IL-12p35 -/- and IL-12p40 -/- but not in STAT4 -/- mice, indicating a IL-12-independent role of STAT4. Furthermore, no significant difference in serum ALT and necrotic lesions were observed when WT or STAT4 -/- spleenocytes were adoptive transfer into lymphocyte deficient Rag2gc -/- mice, suggesting that protection in STAT4 -/- is independent of lymphocyte STAT4. Interestingly, serum IFNg level were significantly reduced in both IL-12p35 -/- and STAT4 -/- mice, and injection of recombinant IFNg into STAT4 -/- mice increase the serum ALT, but it does not reach the level observed in WT mice, suggesting a non-IFNg mediated protection in STAT4 -/- mice. Surprisingly, there were no significant difference in FAS and FasL transcript in ConA injected liver tissue in WT and STAT4 -/- mice. In addition, anti-FAS antibody injections lead to significant necrotic changes in WT, but not in STAT4 -/- mice. Our data strongly indicate absence of STAT4 signaling potentially in hepatocytes regulates cell survival, which is further confirmed by significantly more pSTAT3 staining in liver tissue of STAT4 -/-. STAT3 phosphorylation can be regulated by IL-22 or IL-6. Interestingly, serum IL-22 but not IL-6 was significantly elevated in STAT4 -/- mice. Our data strongly suggest targeting STAT4 in auto-immune hepatitis may have a therapeutic benefit.
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