Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis

Afford, Simon C.; Humphreys, Elizabeth H.; Reid, Danielle T.; Russell, Clare L.; Banz, Vanessa M.; Oo, Ye; Vo, Tina; Jenne, Craig; Adams, David H.; Eksteen, Bertus (2014). Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis. Hepatology, 59(5), pp. 1932-1943. Wiley Interscience 10.1002/hep.26965

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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 a4b1 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 a4b1 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 a4b1, 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 Tcell
survival. Conclusions: VCAM-1 expression by cholangiocytes contributes to persistent
inflammation by conferring a survival signal to a4b1 expressing proinflammatory T
lymphocytes in CLD.

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