David H. Adams and Simon C. Afford

The Liver Research Laboratories, MRC Centre for Immune Regulation, The University of Birmingham Institute of Clinical Science, The Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom

FIGURES

Figure 1. Leukocyte recruitment to the portal tract. Leukocytes are recruited via portal vessels in response to appropriate adhesion molecules and promigratory signals delivered by chemokines including the CCR5 ligands RANTES, MIP-1a and MIP-1b on portal endothelium. The infiltrating cells are localised to the biliary epithelium in bile ducts by chemokines expressed and secreted by cholangiocytes. Non-inflamed cholangiocytes express SDF the chemokine ligand for CXCR4 strongly, and when inflamed secrete several other chemokines including IL-8, RANTES and MCP-1 allowing them to localise effector cells to the epithelial barrier.

Figure 2. In normal non inflamed liver, bile ducts show little evidence of cholangiocyte apoptosis (Panel A). However during sustained inflammation of the portal tract, in cases of PBC or chronic allograft rejection for example, bile ducts surrounded by an inflammatory infiltrate of CD3 +ve T cells and CD14/CD68+ve monocytic cells frequently contain cholangiocytes undergoing apoptosis which are revealed by in situ DNA end labelling methods and nuclear morphology (Panel B).

Figure 3. Activation of CD40 during Liver Inflammation may have complex consequences. CD40 is expressed by a wide range of liver cell types during inflammation (epithelium, macrophages, endothelium, fibroblasts, B cells and dendritic cells) suggesting that it is involved in the promotion of a wide range of cell specific proinflammatory responses. CD40L expression is confined (in human liver tissue) to activated T cells and macrophages. Another important source of CD40L is platelets which may present functional ligand to hepatic endothelium. Synthesis of CD40L by endothelial cells has been reported in vitro, although the significance of this remains to be demonstrated in vivo.

Figure 4. Activated leukocytes have a diverse array of cell surface weaponry with which to directly induce cholangiocyte apoptosis including TNF, Fas ligand, possibly other TNF family members, and the granzyme/perforin system. Autocrine or paracrine Fas-mediated cholangiocyte apoptosis can also be induced via CD40L expressed on activated macrophages or T cells. Which pathway or combination of pathways is utilised will depend upon the inflammatory microinvironment. Soluble forms of TNF family members including FasL and CD40L may exist, although their function in tissues remains unknown. During biliary obstruction and cholestatic liver disease, components of bile can act in a number of ways to exacerbate cholangiocyte death via diverse mechanisms which can involve direct DNA damage, induction of TNFRs or modulation of survival factor translocation to the mitochondrial membrane.