Inhibition of growth hormone action in models of inflammation

Growth hormone (GH) action is attenuated during the hepatic acute-phase res ponse (APR). To understand this attenuation, we asked whether GH and cytoki ne-signaling pathways intersect during an APR. In hypophysectomized rats tr eated with lipopolysaccharide (LPS), accumulation of activated signal trans ducer and transcription activator 5 (Stat5) in hepatic nuclei in response t o GH and its binding to a GH response element (GHRE) from the serine protea se inhibitor (Spi) 2.1 promoter are diminished in a time-dependent manner. Similarly, accumulation of activated Stat3 in hepatic nuclei in response to LPS and its binding to a high-affinity sis-inducible element (SIE) are als o diminished by the simultaneous administration of GH. In functional assays with primary hepatocytes, LPS-stimulated monocyte-conditioned medium (MoCM ) inhibits the GH response of Stat5-dependent Spi 2.1 reporter activity but induces Stat3-dependent Spi 2.2 reporter activity, as in an APR. Similar r esults are obtained when hepatocytes are treated with either tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1 beta. TNF-alpha, IL-1 beta, and IL-6 also inhibit GH-induced Spi 2.1 mRNA expression in hepatocytes. T hus inhibition of the GH signaling pathway during an APR results in reduced expression of GH-responsive genes.