Influence of Kupffer cell inactivation on cycloheximide-induced hepatic injury.
In our previous study, we found that cycloheximide (CHX) induces hepatocellular necrosis as well as hepatocellular apoptosis. This article evaluates the role of Kupffer cells on cycloheximide-induced hepatic injury using gadolinium chloride (GdCl(3)) for the inhibition of Kupffer cells. One group of rats was treated with CHX (CHX group), and another was treated with GdCl(3) before being treated with the same dose of CHX (GdCl(3)/CHX group). The necrotic change in the GdCl(3)/CHX group was exacerbated under the induction of hepatocellular apoptosis by the CHX treatment. A substantial diminution of the number of ED1- or ED2-positive cells was demonstrated in the GdCl(3)/CHX group compared to the CHX group. In addition, the degree of decrease in ED2-positive cells was more apparent than that in ED1-positive cells. Increases in the mRNA levels of IL-10 and Stat3 were observed in the CHX group, but not in the GdCl(3)/CHX group. On the other hand, the hepatic mRNA levels of chemokines and adhesion molecules such as Ccl20, LOX-1, and E-selectin were significantly increased only in the GdCl(3)/CHX group. Thus, Kupffer cell inactivation by the GdCl(3) treatment leads to a loss of the capacity to produce IL-10, supposedly resulting in the enhancement of pro-inflammatory cytokine activities such as tumor necrosis factor (TNF) signaling. These events are suggested to be a factor of the inflammatory exacerbation in the livers of the GdCl(3)/CHX group. In conclusion, Kupffer cells may play a role in protecting hepatic necroinflammatory changes by releasing anti-inflammatory cytokines following the hepatocellular apoptosis resulting from CHX treatment.
Kumagai
Kazuyoshi
K
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan. kumagai.kazuyoshi.k6@daiichisankyo.co.jp
Kiyosawa
Naoki
N
Ito
Kazumi
K
Yamoto
Takashi
T
Teranishi
Munehiro
M
Nakayama
Hiroyuki
H
Manabe
Sunao
S
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D003513:Cycloheximide / Q000633:toxicity*; D005682:Gadolinium / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology; D008111:Liver Function Tests; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011500:Protein Synthesis Inhibitors / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015703:Antigens, CD; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D005682:Gadolinium; C038958:gadolinium chloride