Up-regulation of hepatic heme oxygenase-1 expression by locally induced interleukin-6 in rats administered carbon tetrachloride intraperitoneally

Abstract We previously reported that interleukin-6 (IL-6) was locally produced in the early period after intraperitoneal (i.p.) or subcutaneous carbon tetrachloride (CCl 4 ) 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. CCl 4 administration. The expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3) mRNA and protein were induced more in rats administered CCl 4 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. CCl 4 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. CCl 4 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. CCl 4 . The up-regulation of hepatic HO-1 expression may reduce the tissue injury to livers caused by CCl 4 .