Effects of Kupffer cell inhibition on liver function and hepatocellular activity in mice.
Kupffer cells are the tissue macrophages in the liver and play an important role in the defense mechanisms of the body. However, their role in liver function and hepatocellular activity remains unclear. This study was therefore undertaken to investigate the effect of gadolinium chloride-induced Kupffer cell dysfunction on liver function and hepatocellular signaling activity in mice and to establish an animal model for studying the role of Kupffer cells in vivo. Kunming mice were intraperitoneally injected with different doses of gadolinium chloride (GdCl3), a selective inhibitor of Kupffer cells, and the mice were sacrificed at different time periods following the drug administration. Hepatotoxicity and Kupffer cell function, as well as the levels of signaling molecules and inflammatory mediators in liver tissue, were measured. We demonstrated that the administration of 10-20 mg/kg GdCl3 caused apoptosis of Kupffer cells and blocked the Kupffer cell effector function, as shown by a decrease in CD68 expression and phagocytic activity. In addition, the NO, PGE2 and cAMP levels in the liver were also reduced significantly. Furthermore, 20 mg/kg GdCl3 decreased the levels of cNOS, PKC and NF-kappaB p65 expression by 26.6, 68 and 64%, respectively. In contrast, hepatotoxicity was not observed when the same doses of GdCl3 were used. Moreover, we found that Kupffer cell function and the NO, PGE2 and cAMP contents, as well as PKC and NF-kappaB p65 levels in the liver were only partially, but not fully recovered in up to six days following 20 mg/kg GdCl3 injection. However, the administration of higher doses of GdCl3 (40 mg/kg) caused both hepatotoxicity and Kupffer cell necrosis, as well as an increased release of TNF, NO, and PGE2 in the liver. These results indicate that administration of suitable doses of GdCl3 blocked the effector function of Kupffer cells selectively, but did not cause liver parenchymal cell toxicity, and provide a frame-work for the establishment of an animal model for studying the role of Kupffer cells in signaling in the liver. Lastly, the present study also provides evidence that shows there is a positive association between the expression of cAMP, PKC, or NF-kappaB and the levels of NO, PGE2 and TNF in the liver of Kupffer-cell-blocked mice, and suggests that Kupffer cells may play a part in mediating liver function and hepatocellular activity.
Ding
Hong
H
Wuhan University College of Pharmacy, Wuhan, Hubei 430071, P.R. China.
Peng
Renxiu
R
Reed
Eddie
E
Li
Qingdi Q
QQ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D017209:Apoptosis; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007728:Kupffer Cells / Q000378:metabolism* / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008854:Microscopy, Electron; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010587:Phagocytosis; D015398:Signal Transduction; D013997:Time Factors; D000097382:CD68 Molecule
D000251:Adenosine Triphosphatases; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000242:Cyclic AMP; D015232:Dinoprostone; D005682:Gadolinium; D006003:Glycogen; D016328:NF-kappa B; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C038958:gadolinium chloride