Role of heme oxygenase-1 and Kupffer cells in the production of bilirubin in the rat liver.
Heme oxygenase (HO)-1, the heme-degrading enzyme in macrophages, plays a key role in bilirubin metabolism. HO-1 is expressed in various tissue macrophages, especially Kupffer cells. This study aimed to examine the roles of macrophages and HO-1 in the modulation of heme catabolism in rat livers. Rats treated with or without liposome-encapsulated dichloromethylene diphosphonate, a macrophage-depleting reagent, were administered with heat-denatured red blood cells (h-RBC), and the time course of the biliary output of bilirubin and the expressions of HO-1 mRNA and protein were monitored. Immunohistochemistry in the control rat liver revealed that Kupffer cells constitute a major cellular component expressing HO-1, while hepatocytes exhibited little expression. The levels of HO-1 expression in Kupffer cells were elevated immediately after injection of h-RBC. In Kupffer cell-depleted livers, however, HO-1-expressing cells were not detected even after h-RBC administration. HO-1 mRNA levels were elevated at 2 h after administration of h-RBC in control rat livers, while they were very low in Kupffer cell-depleted rat livers. The control and Kupffer cell-depleted groups exhibited distinct time courses of biliary bilirubin excretion. In the untreated control rats, total bilirubin excretion increased about two-fold at 5 h after h-RBC administration. In contrast, the Kupffer cell-depleting treatment decreased the level of bilirubin production; administration of h-RBC to Kupffer cell-depleted rats did not accelerate the generation of bilirubin. These results suggest that Kupffer cells serve both as a sensor for scenesent RBC clearance and an effector that upregulates heme-degrading capacity and bilirubin production.
Hirano
K
K
Second Department of Pathology, Niigata University School of Medicine, Japan.
Kobayashi
T
T
Watanabe
T
T
Yamamoto
T
T
Hasegawa
G
G
Hatakeyama
K
K
Suematsu
M
M
Naito
M
M
D000818:Animals; D001663:Bilirubin / Q000096:biosynthesis*; D004912:Erythrocytes / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000502:physiology*; D006358:Hot Temperature; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000201:enzymology*; D008081:Liposomes; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D016253:Microscopy, Immunoelectron; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D008081:Liposomes; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin