In order to identify an endogenous bioactive substance(s) which are involved in the chronic phases of inflammation in liver, we analyzed several liver dysfunction models in mice from molecular pathological viewpoints.
#1. We proved that interferon (IFN)-γ regulated the production of pro-inflammatory cytokines and the infiltration of inflammatory cells including neutrophils and macrophages, thereby contributing to the development of lipopolysaccharide (LPS)-induced acute liver injury in Propioniobaciterium acnes-primed mice and acetaminophen-induced acute fatal liver dysfunction.
#2. We obtained the evidence to suggest that interleukin (IL)-6 have bifacial roles in carbon tetrachloride-induced chronic liver fibrosis; induction of fibrogenic process and maintenance of the hepatocyte capacity to produce serum proteins such as albumin, by up-regulating the expression of a potent fibrogenic factor, transforming growth factor-β_1 and hepatocyte growth factor, respectively.
#3. We have provided evidence that tumor necrosis factor receptor p55-mediated signals regulated the accumulation of Kupffer and Ito cells, thereby inducing liver fibrosis.
#4. We observed that intrasplenic injection of tumors induced TNF-α expression and subsequent vascular adhesion molecule-1 expression in sinusoidal endothelial cells in liver, thereby inducing liver metastasis.
#5. We observed that CCL3, induced by endogenously produced IL-1, might interact with its specific receptor, CCR1, constitutively expressed on hepatoma cells, in human hepatoma tissues.
We are in the process to analyze the gene expression patterns between wild-type and various types of cytokine-related gene-deficient mice in the above mentioned inflammation models, in order to identify the molecule(s) which is crucially involved in the development of chronic liver inflammation.