The gene encoding ␣-1-acid glycoprotein (AGP), one of the major acute-phase proteins, is positively controlled at the transcriptional level by cytokines (interleukin-1 [IL-1], IL-6, and tumor necrosis factor ␣) and glucocorticoids. Here, we show that growth hormone (GH) treatment of isolated rat hepatocytes in vitro reduces AGP messenger RNA (mRNA) expression. AGP gene expression remained inducible by IL-1, IL-6, and phenobarbital (PB) in GHtreated hepatocytes. Interestingly, the repressive effect of GH on AGP gene expression was also observed in vivo: liver AGP mRNA content was strongly increased in hypophysectomized rats, and GH treatment of these animals led to a decrease in mRNA to levels lower than those in untreated control animals. Moreover, the inhibitory effect of GH mainly occurs at the transcriptional level and can be observed as little as 0.5 hours after GH adding in vitro to isolated hepatocytes. These results show negative regulation of AGP gene expression and strongly suggest that GH is a major endogenous regulator of constitutive AGP gene expression. Moreover, transfection assays showed that the region of the AGP promoter located at position ؊147 to ؊123 is involved in AGP gene regulation by GH. ␣-1-Acid glycoprotein (AGP), which is mainly secreted by hepatocytes, is a major acute-phase reactant in humans, mice, and rats: Its serum concentration increases markedly in response to inflammation and infection. 1 AGP gene transcription appears to be regulated by both endogenous and exogenous factors. During an acute-phase reaction, rat liver AGP is transcriptionally activated by glucocorticoids, interleukin-1 (IL-1), and IL-6. 2-3 IL-1 and IL-6 activity is mediated by DNA sequences known as distal-responsive elements located between positions Ϫ5300 and Ϫ5150 relative to the transcriptional start site. 3,4 Glucocorticoids act through a glucocorticoid-responsive element (GRE), which is in close proximity to the transcription start site at position Ϫ122 to Ϫ108. 5,6 Another functional sequence located at Ϫ155 to Ϫ143, called the upstream-responsive element, is required for glucocorticoid regulation. 7 The distal-responsive element, GRE, and upstream-responsive element contain binding sites for members of the C/EBP factor family. 7-10 Phenobarbital (PB) also induces AGP production by a mechanism independent of the inflammatory pathway 11 and acts at the transcriptional level through a PB-responsive element located between the GRE and the upstream-responsive element at position Ϫ142 to Ϫ126. 12 A similar responsive element has been described in the promoter region of CYP2B1 and 2B2 and is involved in the induction of these genes by PB. 13 Moreover, growth hormone (GH) suppresses both constitutive and PB-induced expression of CYP2B1 and CYP2B2. [14][15][16]
