Potential conflict of interest: Nothing to report.
Autoimmune, Cholestatic and Biliary Disease
Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis
Article first published online: 27 MAR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 5, pages 1932–1943, May 2014
How to Cite
Afford, S. C., Humphreys, E. H., Reid, D. T., Russell, C. L., Banz, V. M., Oo, Y., Vo, T., Jenne, C., Adams, D. H. and Eksteen, B. (2014), Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis. Hepatology, 59: 1932–1943. doi: 10.1002/hep.26965
This work was supported by unrestricted grants from The Medical Research Council, British Liver Trust, American Liver Foundation, and the National Institute for Health Research.
- Issue published online: 23 APR 2014
- Article first published online: 27 MAR 2014
- Accepted manuscript online: 12 DEC 2013 01:39AM EST
- Manuscript Accepted: 4 DEC 2013
- Manuscript Received: 16 JUL 2013
Chronic hepatitis occurs when effector lymphocytes are recruited to the liver from blood and retained in tissue to interact with target cells, such as hepatocytes or bile ducts (BDs). Vascular cell adhesion molecule 1 (VCAM-1; CD106), a member of the immunoglobulin superfamily, supports leukocyte adhesion by binding α4β1 integrins and is critical for the recruitment of monocytes and lymphocytes during inflammation. We detected VCAM-1 on cholangiocytes in chronic liver disease (CLD) and hypothesized that biliary expression of VCAM-1 contributes to the persistence of liver inflammation. Hence, in this study, we examined whether cholangiocyte expression of VCAM-1 promotes the survival of intrahepatic α4β1 expressing effector T cells. We examined interactions between primary human cholangiocytes and isolated intrahepatic T cells ex vivo and in vivo using the Ova-bil antigen-driven murine model of biliary inflammation. VCAM-1 was detected on BDs in CLDs (primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic liver disease, and chronic hepatitis C), and human cholangiocytes expressed VCAM-1 in response to tumor necrosis factor alpha alone or in combination with CD40L or interleukin-17. Liver-derived T cells adhered to cholangiocytes in vitro by α4β1, which resulted in signaling through nuclear factor kappa B p65, protein kinase B1, and p38 mitogen-activated protein kinase phosphorylation. This led to increased mitochondrial B-cell lymphoma 2 accumulation and decreased activation of caspase 3, causing increased cell survival. We confirmed our findings in a murine model of hepatobiliary inflammation where inhibition of VCAM-1 decreased liver inflammation by reducing lymphocyte recruitment and increasing CD8 and T helper 17 CD4 T-cell survival. Conclusions: VCAM-1 expression by cholangiocytes contributes to persistent inflammation by conferring a survival signal to α4β1 expressing proinflammatory T lymphocytes in CLD. (Hepatology 2014;59:1932–1943)