Up-regulation of hepatic heme oxygenase-1 expression by locally induced interleukin-6 in rats administered carbon tetrachloride intraperitoneally.
We previously reported that interleukin-6 (IL-6) was locally produced in the early period after intraperitoneal (i.p.) or subcutaneous carbon tetrachloride (CCl4) administration, but not after oral (p.o.) administration. In the present study, we focused on the up-regulation of stress-inducible proteins induced by IL-6 after i.p. CCl4 administration. The expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3) mRNA and protein were induced more in rats administered CCl4 via the i.p. route, compared with the p.o. route; however, expression of heat shock protein (HSP) 72 and HSP90 mRNA were increased to similar extents in both experimental groups. The induction of HO-1 mRNA and protein after i.p. CCl4 administration were significantly reduced after pretreatment with anti-rat IL-6 antibody. Activation of the signal transducer and activator of transcription factor 3 (STAT3), which promotes HO-1 expression, peaked together with plasma levels of IL-6 after i.p. CCl4 administration, suggesting that hepatic HO-1 expression was increased by IL-6 via the Janus kinase/STAT3 pathway. The present data indicate that hepatic HO-1 is up-regulated by endogenously produced IL-6, in addition to its up-regulation by heme derived from cytochrome P450 which has already been reported in rats administered i.p. CCl4. The up-regulation of hepatic HO-1 expression may reduce the tissue injury to livers caused by CCl4.
Department of Hygienic Chemistry, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo, Japan.
Kenzaburo
K
Yamaji
Yosuke
Y
Ochiai
Ken-ichi
K
Ohnishi
Ayako
A
Yawata
Toshiyuki
T
Chikuma
Hiroshi
H
Hojo
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity*; D004306:Dose-Response Relationship, Immunologic; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
D019138:Antibodies, Blocking; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D002251:Carbon Tetrachloride; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat