Regulation of hepatic cytochrome P450 2C11 by transforming growth factor-beta, hepatocyte growth factor, and interleukin-11.
Injection of rats with bacterial lipopolysaccharide down-regulates P450 (P450) 2C11 (2C11) mRNA to about 20% of its control levels after only 6 hr, and this level is maintained for at least 48 hr. Although we and others have demonstrated that this effect may be at least partially mediated by the cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha, as well as by glucocorticoids, the time courses and potencies of 2C11 repression by each single mediator suggested that no cytokine alone is responsible for the entire time course of 2C11 suppression during inflammation. Here, we show that transforming growth factor-beta, hepatocyte growth factor, and interleukin-11 are potent inhibitors of 2C11 expression. In all three cases, 0.1 ng/ml was enough to down-regulate 2C11 mRNA levels to 50% of control. Interleukin-8, a cytokine that is secreted during the acute phase response but does not influence the liver acute phase response, did not affect 2C11 expression. The various mediators have different time courses of 2C11 down-regulation, indicating that the roles of each may be different at different phases of the response.
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
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D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D017370:Interleukin-11 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D017370:Interleukin-11; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase