Neutralization of IL-10 exacerbates cycloheximide-induced hepatocellular apoptosis and necrosis.
Cycloheximide (CHX)-induced liver injury in rats has been characterized by hepatocellular apoptosis and necrosis. We previously reported that Kupffer cell inactivation causes a reduction of IL-10 production, resulting in the exacerbation of CHX-induced liver injury. In this study, we directly evaluate the role of IL-10 in liver injury by a pretreatment with anti-IL-10 neutralizing antibody (IL-10Ab). Rats were given goat IgG or IL-10Ab before being treated with CHX (CHX group or IL-10Ab/CHX group). In the CHX group, the CHX treatment markedly induced hepatic mRNA and serum protein levels of IL-10. The up-regulation of IL-10 was significantly suppressed in the IL-10Ab/CHX group. Blocking IL-10 in the IL-10Ab/CHX group led to greater increases in hepatic mRNA and serum levels of proinflammatory cytokines, such as TNF-alpha and IL-6. The IL-10Ab/CHX group developed more severe hepatocellular apoptosis, neutrophil transmigration, and necrotic change of hepatocytes compared with the CHX group. The caspase activities and mRNA levels of Cc120, LOX-1, and E-selectin in the livers were significantly higher in the IL-10Ab/CHX group than the CHX group. These results demonstrate that IL-10 plays an important role in counteracting the effect of proinflammatory cytokines, such as a TNF signaling cascade, and in attenuating the CHX-induced liver injury.
Kumagai
Kazuyoshi
K
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka 437-0065, Japan. kumagai.kazuyoshi.k6@daiichisankyo.co.jp
Ito
Kazumi
K
Ando
Yosuke
Y
Hakamata
Shinobu
S
Teranishi
Munehiro
M
Nakayama
Hiroyuki
H
Manabe
Sunao
S
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D003513:Cycloheximide / Q000008:administration & dosage / Q000633:toxicity*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003627:Data Interpretation, Statistical; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology / Q000473:pathology; D008297:Male; D009336:Necrosis; D009500:Neutralization Tests; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D015854:Up-Regulation
D000906:Antibodies; D016207:Cytokines; D012333:RNA, Messenger; D016753:Interleukin-10; D003513:Cycloheximide; D020169:Caspases