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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.

SUMMARYControversy exists over the scaling of oxygen consumption with body mass in vertebrates. A combination of biochemical and structural analyses were used to examine whether individual elements influencing oxygen delivery and demand within locomotory muscle respond similarly during ontogenetic growth of striped bass. Mass-specific metabolic enzyme activity confirmed that glycolytic capacity scaled positively in deep white muscle (regression slope, b0.1 to 0.8) over a body mass range of ~20-1500g, but only creatine phosphokinase showed positive scaling in lateral red muscle (b0.5). Although oxidative enzymes showed negative allometry in red muscle (b-0.01 to -0.02), mass-specific myoglobin content scaled positively (b0.7). Capillary to fibre ratio of red muscle was higher in larger (1.42±0.

The ability to regulate vascular tone is an essential cardiovascular control mechanism, with nitric oxide (NO) assumed to be a ubiquitous smooth muscle relaxant. However, the literature contains reports of vasoconstrictor, vasodilator and no response to nitroergic stimulation in non-mammalian vertebrates. We examined functional (branchial artery myography), structural (immunohistochemistry of skeletal muscle), proteomic (Western analysis) and genomic (RT-PCR, sequence orthologues, syntenic analysis) evidence for endothelial NO synthase (NOS3) in model and non-model fish species. A variety of nitrodilators failed to elicit any changes in vascular tone, although a dilatation to exogenous cyclic GMP was noted. NOS3 antibody staining does not localise to endothelial markers in cryosections, and gives rise to non-specific staining of Western blots. Abundant NOS2 mRNA was found in all species but NOS3 was not found in any fish, while putative orthologues are not flanked by similar genes to NOS3 in humans. We conclude that NOS3 does not exist in fish, and that previous reports of its presence may reflect use of antibodies raised against mammalian epitopes.