Overexpression of TNFα in TNF∆ARE+/- mice increases hepatic periportal inflammation and alters bile acid signaling in mice.

BACKGROUND

Intestinal inflammation is a common factor in ~70% of patients diagnosed with primary sclerosing cholangitis. The TNF∆ARE+/- mouse overexpresses TNFα and spontaneously develops ileitis after weaning. The aim of this study was to examine the influence of ileitis and TNFα overexpression on hepatic injury, fibrosis, inflammation, and bile acid homeostasis.

METHODS

Using serum, hepatic, and ileal tissue isolated from 24- to 26-week-old C57BL/6 and TNF∆ARE+/- mice, hepatic injury and fibrosis, inflammation, ductal proliferation, and regulation of bile acid synthesis were assessed by immunohistochemical and quantitative PCR methods.

RESULTS

Compared to age-matched C57BL/6 mice, TNF∆ARE+/- mice exhibited increased serum AST, ALT, and serum bile acids, which corresponded to increased hepatic picrosirius red staining, and an increase in hepatic mRNA expression of Tgfb, Timp1, Col1a1, and MMP9 supporting induction of fibrosis. Examining inflammation, immunohistochemical staining revealed a significant periportal increase in MPO+ neutrophils, CD3+ lymphocytes, and a panlobular increase in F4/80+ macrophages. Importantly, periportal inflammation corresponded to significantly increased proinflammatory chemokines as well as hepatic cytokeratin 7 staining supporting increased ductular proliferation. In the liver, increased mRNA expression of bile acid transporters was associated with suppression of classical but not alternative bile acid synthesis. In the ileum, increased inflammation correlated with suppression of Nr1h4 and increased Fgf15 and Nr0b2 mRNA expression.

CONCLUSIONS

Increased TNFα expression is sufficient to promote both intestinal and hepatobiliary inflammation and fibrotic injury and contributes to hepatic dysregulation of FXR signaling and bile acid homeostasis. Overall, these results suggest that the TNF∆ARE+/- mouse may be a useful model for studying chronic hepatic inflammation.