Study on the regulation mechanism by endogenous bioactive substances produced by hepato-sinusoidal cells.

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Hepatic sinusoidal cells are mainly constituted by Kupffer cells, hepatic sinusoidal endothelial cells, Ito cells and pit cells. In this study, we focused Kupffer cells and hepatic sinusoidal endothelial cells to analyze the role of endogenous activating substances on the regulation network in the liver.1) The production of arachidic acid metabolites and lipid metabolites by hepatic sinusoidal cells. Once rat Kupffer cells were stimulated by biological response modifiers such as lipopolysaccharide (LPS), heat-killed Propionibacterium acnes (P. acnes) and OK-432, they produced and secreted prostaglandin (PG) E2, 6-keto PGF1alpha and thromboxane (TX)B2. However, they produced PGD2 in rest state. This change was due to the induction of cyclo-oxygenase that is located on the upstream of the PG metabolic pathway. The stimulated Kupffer cells did not produce such PG metabolites unless they were inculated without Ca^<2+>, or with Ca^<2+>-chylates or calmodulin inhibitors, suggesting that their production by stimulated Kupffer cells might depend on intracellular and extracellular Ca as well as calmodulin. When Kupffer cells and hepatic sinusoidal endothelial cells were incubated with Ca ionophore, they produced platelet activating factor (PAF), a biological active lipid metabolite.2) Cytokines produced by hepatic sinusoidal cells. LPS-stimulated Kupffer cells produced interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha. This was also obsereved by stimulated hepatic sinusoidal endothelial cells. Interferon-gamma, a macrophage activating factor, led Kupffer cells to produce these cytokines, while PGE1 or PGI2 reduced such cytokine production. These results suggested the existence of the inter-and intra-regulation systems among cytokine network and arachidic acid metabolite cascade in the hepatic sinusoidal cells.