TNF-α is essential in the induction of fatal autoimmune hepatitis in mice through upregulation of hepatic CCL20 expression

It is unclear what roles TNF-alpha has in the development of autoimmune hepatitis (AIH) and whether AIH is responsive to anti-TNF-alpha. We recently developed a mouse model of fatal AIH that develops in PD-1-deficient mice thymectomized three days after birth, finding that CCR6-CCL20 axis-dependent migration of dysregulated splenic T cells is crucial to induce AIH. In this study, we show the indispensable role of TNF-alpha in the development of AIH. Administering anti-TNF-alpha prevented the induction, but treatment by anti-TNF-alpha after the induction did not suppress progression. Administering anti-TNF-alpha did not prevent splenic T-cell activation, but did suppress hepatic CCL20 expression. In contrast, administering anti-CCL20 suppressed AIH but not elevated serum TNF-alpha levels. TNF-alpha stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNF-alpha is essential in the induction of AIH through upregulation of hepatic CCL20 expression, which allows migration of dysregulated splenic T cells. (C) 2012 Elsevier Inc. All rights reserved.