C4b binding protein binds to CD154 preventing CD40 mediated cholangiocyte apoptosis: a novel link between complement and epithelial cell survival

• Published in: PloS one Vol. 2; no. 1; p. e159
• Main Authors: Williams, Kevin T, Young, Steven P, Negus, Alison, Young, Lawrence S, Adams, David H, Afford, Simon C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.01.2007; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Apoptosis; Apoptosis - immunology; B cells; Bile; Biochemistry; Biomedical research; C4b-binding protein; CD40 antigen; CD40 Antigens - immunology; CD40 Ligand - immunology; CD40L protein; Cell activation; Cell Biology; Cell Biology/Cell Growth and Division; Cell Biology/Cell Signaling; Cell Biology/Cellular Death and Stress Responses; Cell growth; Cell Proliferation; Cell surface; Cell survival; Cell Survival - immunology; Cells, Cultured; Complement; Complement activation; Complement C4b-Binding Protein - immunology; Complement System Proteins - immunology; Coordination compounds; Cytokines; Epithelial cells; Epithelial Cells - immunology; Gastroenterology and Hepatology; Gastroenterology and Hepatology/Biliary Tract; Gastroenterology and Hepatology/Gastrointestinal Cancers; Gel filtration; Gene expression; Hepatocytes; Humans; Immune system; Immunohistochemistry; Intracellular signalling; JNK Mitogen-Activated Protein Kinases - immunology; Ligands; Liver; Liver - cytology; Liver - immunology; Liver cancer; Liver diseases; Localization; Medical research; Molecular weight; NF-kappa B - immunology; NF-κB protein; Prevention; Protein binding; Protein synthesis; Proteins; Proto-Oncogene Proteins c-fos - immunology; Receptors; Rodents; Signal transduction; STAT3 Transcription Factor - immunology; Surface Plasmon Resonance; Survival; TNF inhibitors; Transcription factors; Tumor necrosis factor; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000159

Activation of CD40 on hepatocytes and cholangiocytes is critical for amplifying Fas-mediated apoptosis in the human liver. C4b-Binding Protein (C4BP) has been reported to act as a potential surrogate ligand for CD40, suggesting that it could be involved in modulating liver epithelial cell survival. Using surface plasmon resonance (BiaCore) analysis supported by gel filtration we have shown that C4BP does not bind CD40, but it forms stable high molecular weight complexes with soluble CD40 ligand (sCD154). These C4BP/sCD154 complexes bound efficiently to immobilised CD40, but when applied to cholangiocytes they failed to induce apoptosis or proliferation or to activate NFkB, AP-1 or STAT 3, which are activated by sCD154 alone. Thus C4BP can modulate CD40/sCD154 interactions by presenting a high molecular weight multimeric sCD154/C4BP complex that suppresses critical intracellular signalling pathways, permitting cell survival without inducing proliferation. Immunohistochemistry demonstrated co-localisation and enhanced expression of C4BP and CD40 in human liver cancers. These findings suggest a novel pathway whereby components of the complement system and TNF ligands and receptors might be involved in modulating epithelial cell survival in chronic inflammation and malignant disease.