Highly liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachloride-induced hepatotoxicity.
Heme oxygenase (HO)-1, the rate-limiting enzyme in heme catabolism, can be induced in response to various oxidative stimuli, and its induction is thought to be critical in the cellular defense against oxidative tissue injuries. Carbon tetrachloride (CCl(4)) treatment of rats causes lipid peroxidation of cell membranes and produces massive hepatic injury. We previously demonstrated that HO-1 induction following CCl(4) treatment is an essential part of the cellular defense against the CCl(4)-inducible toxic changes. As recombinant human interleukin-11 (rhIL-11) has been shown to induce HO-1 in cultured hepatoma cells, we examined the effect of rhIL-11 in vivo in rats on the CCl(4)-induced tissue injury. rhIL-11 treatment of animals by itself markedly induced HO-1 mRNA and its functional protein principally in the liver. rhIL-11 treatment (150 microg/kg) of the CCl(4)-administered (1 ml/kg) animals led to a further increase in HO-1 mRNA, while it markedly suppressed CCl(4)-induced serum alanine transaminase, hepatic malondialdehyde formation, tumor necrosis factor-alpha mRNA, nitric oxide synthase mRNA, nuclear factor-kappaB DNA-binding activity, as well as inflammatory changes of hepatocytes. In contrast, inhibition of HO activity by tin-mesoporphyrin, a competitive specific inhibitor of HO, entirely abolished the cytoprotective effect of rhIL-11. These findings thus demonstrate that rhIL-11 confers significant protection against CCl(4)-induced hepatic injury by virtue of its liver-specific HO-1 induction.
Kawakami
Tomoko
T
Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama 700-8558, Japan.
Takahashi
Toru
T
Shimizu
Hiroko
H
Nakahira
Kiichi
K
Takeuchi
Mamoru
M
Katayama
Hiroshi
H
Yokoyama
Masataka
M
Morita
Kiyoshi
K
Akagi
Reiko
R
Sassa
Shigeru
S
D000818:Animals; D015152:Blotting, Northern; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D007275:Injections, Intravenous; D017370:Interleukin-11 / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008107:Liver Diseases / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D017370:Interleukin-11; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D002251:Carbon Tetrachloride; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1