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

Abstract

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)

Immune signatures of pathogenesis in the peritoneal compartment during early infection of sheep with Fasciola hepatica

“…This is consistent with other studies showing an increase in VCAM-1 expression associated with chronic liver and biliary diseases 73 . As observed in this study, VCAM-1 expression is low in resting, undamaged cells but during liver inflammation its expression increases, and is believed to be important for recruitment of monocytes and lymphocytes 74–76 .…”

Imbalance of regulatory T cells and T helper type 17 cells in patients with chronic hepatitis C

“…26,27 More recently, Wang et al 28 reported that the up-regulation of IL-17 production in CD4 + T cells in chronic hepatitis C patients, and elevated Tim-3 signalling on CD14 + monocytes impaired the balance of IL-12/IL-23 through the intracellular signal transducer and activator of transcription 3 signalling, which led to the IL-17 secretion and Th17 cell development. Afford et al 29 also confirmed that vascular cell adhesion molecule 1 (VCAM-1) promotes liver inflammation by inducing lymphocyte recruitment and Th17 cell survival. Those studies revealed the association between Th17 cells and liver inflammation.…”

Pathogenesis and clinical spectrum of primary sclerosing cholangitis

“…IL-2 receptor α gene deficiency in mice causes biliary inflammation resembling PSC[40]. Integrin ligands, intracellular adhesions molecule 1, and vascular cell adhesion molecule 1 are also expressed by the biliary epithelium and contribute to the recruitment of inflammatory leukocytes that play a role in development of biliary inflammation seen in PSC[41]. Gut-specific T and B cells can be programmed to perpetuate biliary inflammation after encountering an enteric pathogen, providing an important rationale of how liver and gut inflammation may be linked[42].…”