Link Between Sulfhydryl Oxidase Activity And Cytokine Effect Of Hepatopoietin

Normal liver has the unique capacity to regulate its growth in an exquisite homeostatic mechanism, maintaining constant tissue mass relative to levels of metabolic stress in the body. This property is particularly remarkable because hepatocytes as cells rarely divide in their normal state. In both small mammals and humans, throughout the life of the organism, hepatocytes, the main functional cell of the organ, retain a remarkable capacity to adjust to changes in metabolic demand by cell mitosis in the event of a metabolic deficit, or alternatively, through the apoptosis in the event of excess metabolic capacity. Following hepatectomy, liver "knows" when to start and when to stop growing, and thereby accurately regulates its mass. However, "stem-like" cells proliferate when hepatocyte replication is blocked or delayed. Detailed studies of the mechanisms that regulate liver growth have been done in animals subjected to partial hepatectomy or chemical injury. Substantial progress has been achieved using appropriate transgenic and geneknock-out mouse models for this issue. Gene expression in the regenerating liver can be divided into several phases, starting with expression of a large number of immediate early genes. Hepatocytes need to be primed before they can fully respond to the growth factors such as hepatocyte growth factor, transforming growth factor alpha and epidermal growth factor in vitro. Priming requires the cytokines TNF (tumor necrosis factor) and IL-6 (interleukin-6) in addition to other agents that prevent cytotoxicity. Reactive oxygen species and glutathione content can determine whether the TNF effect on hepatocytes is proliferative or apoptotic. At least three transcription factors, NFκB, STAT3 (signal transducer and activator of transcription,STAT) and AP-1 play major roles in the initiation of liver regeneration. Knowledge about the mechanisms of liver regeneration can now be applied to correct clinical problems caused by deficient liver growth.Hepatopoietin (HPO)/ALR (augmenter of liver regeneration) is a novel human hepatotrophic growth factor. Since LaBrecque et al. first reported HSS (hepatic stimulator substance) in 1975, HPO has recently been the subject of intense investigation. Recombinant HPO can stimulate proliferation of hepatocytes as well as hepatoma cells in vitro, promote liver regeneration and recovery of damaged hepatocytes, and rescue acute hepatic failure in vivo. In 1999, we identified the existenceof HPO specific receptor on the surface of these cells (hepatocytes and hepatoma cells). Furthermore, we elucidated that extracellular HPO stimulates proliferation of hepatocytes and enhance liver regeneration by activating the MAPK signaling pathway under the mediation of HPO receptor. And then, we further found that the intracellular HPO can specifically modulate AP-1 pathway through JAB1 via a MAPK-independent pathway and that HPO enhances the increased phosphorylation level of c-Jun through JAB1 but has no effects on the expression of transfected c-Jun, endogenous JNK (c-Jun N-terminal kinase), and phosphorylation of JNK.Cytokines and growth factors stimulate AP-1 activity through several pathways, whereas the intracrine HPO regulates AP-1 transcriptional activity by additional mechanism different from other cytokines and growth factors with mitogenic effects. It seems to be a bit weird that intracellular and extracellular cytokine HPO have dissimilar actions in signal transduction. Recently, it was reported that ERV1/HPO family belonged to sulfhydryl oxidase that is participating in the disulfide bonds formation. The SOX proteins contain a conserved CXXC motif and a non-covalent FAD adjacent to CXXC, which are vital to their catalytic activity. Sulfhydryl oxidases generally form dimers in vivo and catalyze the oxidation of sulfhydryl groups to disulfides according tothe following general reaction, 2 R-SH + O2 → R-S-S-R + H2O2, which is different from the flavoprotein families. HPO also has the CXXC motif and the homodimer form in vitr...