title: C4b binding protein binds to CD154 preventing CD40 mediated cholangiocyte apoptosis: a novel link between complement and epithelial cell survival.
abstract: 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.
authors.affiliation: The Liver Research Group and MRC Centre for Immune Regulation, Institute of Biomedical Research, The University of Birmingham, Birmingham, United Kingdom.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Williams
authors.forename: Steven P
authors.initials: SP
authors.lastname: Young
authors.forename: Alison
authors.initials: A
authors.lastname: Negus
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Simon C
authors.initials: SC
authors.lastname: Afford
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology*; D002478:Cells, Cultured; D050716:Complement C4b-Binding Protein / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D008099:Liver / Q000166:cytology* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D016760:Proto-Oncogene Proteins c-fos / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D020349:Surface Plasmon Resonance
chemical_list: D019013:CD40 Antigens; D050716:Complement C4b-Binding Protein; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D023201:CD40 Ligand; D003165:Complement System Proteins; D048031:JNK Mitogen-Activated Protein Kinases