Interleukin-6-Induced STAT3 and AP-1 Amplify Hepatocyte Nuclear Factor 1-Mediated Transactivation of Hepatic Genes, an Adaptive Response to Liver Injury

Abstract

Following hepatic injury or stress, gluconeogenic and acute-phase response genes are rapidly upregulated to restore metabolic homeostasis and limit tissue damage. Regulation of the liver-restricted insulin-like growth factor binding protein 1 (IGFBP-1) gene is dramatically altered by changes in the metabolic state and hepatectomy, and thus it provided an appropriate reporter to assess the transcriptional milieu in the liver during repair and regeneration. The cytokine interleukin-6 (IL-6) is required for liver regeneration and repair, and it transcriptionally upregulates a vast array of genes during liver growth by unknown mechanisms. The liver, which plays an important role in maintaining metabolic and synthetic homeostasis, constitutes a conditional renewal system in which parenchymal cells normally in G 0 may be induced to proliferate following toxic damage, hepatitis, and surgical resection that culminates in the rapid restoration of hepatic parenchyma (35). To maintain glucose balance following the acute loss of liver mass posthepatectomy, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and other genes involved in gluconeogenesis are rapidly upregulated in the regenerating liver (14, 37, 54, 55). However, the molecular mechanism by which the liver maintains metabolic homeostasis despite the acute loss of twothirds of hepatic tissue or after injury is not known.Liver regeneration, a hyperplastic response, involves the proliferation of the mature functioning cells composing the intact organ (35,54,55). Of the known cytokines released after liver injury or hepatectomy, interleukin-6 (IL-6) has been shown to be required for normal liver regeneration and repair (8,24). In IL6 Ϫ/Ϫ mice, a highly significant reduction in hepatocyte DNA synthesis, increased liver necrosis, discrete G 1 -phase abnormalities including absence of STAT3 activation, reduction in AP-1 activation, and selective abnormalities in gene expression are observed posthepatectomy and after carbon tetrachloride injury, all of which are corrected by injection with IL-6.Among those genes whose expression is abnormal in IL-6 Ϫ/Ϫ livers after partial hepatectomy are those encoding proteins involved in cell cycle progression such as AP-1 factors, c-Myc, and cyclin D1. However, a number of other genes with less clear connection to cell growth show blunted induction in the absence of IL-6, including the insulin-like growth factor binding protein 1 (IGFBP-1) gene. The mechanism by which IL-6 activates such a vast array of genes is unknown. We chose to study IGFBP-1 because of its proposed role in both hepatic growth and metabolism.IGFBP-1 is an immediate-early gene induced at the transcriptional level in the remnant liver following partial hepatectomy (26,38,50). It is distinct in that its plasma level is dynamically regulated by changes in the metabolic state and after hepatic injury. Of the known upregulators of IGFBP-1 transcription, only IL-6 and phorbol esters have been demonstrated to overcome the strong inhibition of IGFB...

Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

“…During liver regeneration, liver cells are exposed to stresses associated with functional deficiency, and these stresses ultimately lead to cell proliferation (9,19,20). We have identified 19 immediate-early transcription-factor genes that are differentially regulated during the priming phase (Table 1), many of which overlap with previously established immediate-early genes implicated by Taub and coworkers (8,15) and Fausto and coworkers (3,(10)(11)(12) that have established the importance of inflammation and protooncogenes in the early stages of liver regeneration.…”

“…In addition, we observed up-regulation of the insulin-like growth factor-binding protein (IGFBP-1), which is induced by IL-6 and HGF, and is known to be up-regulated during the course of liver regeneration (59). IGFBP-1 shares common promoter elements with other hepatic genes associated with the maintenance of metabolic homeostasis following large functional deficiency after PHx such as G6Pase (20).…”

Insulin-mediated activation of activator protein-1 through the mitogen-activated protein kinase pathway stimulates collagenase-1 gene transcription in the MES 13 mesangial cell line

“…These include binding sites for chicken ovalbumin upstream promoter-transcription factor and hepatocyte nuclear factor-1. Both of these factors are expressed in the kidney (Baumhueter et al 1990, Suzuki et al 2000 and both have been previously shown to physically interact with members of the AP-1 transcription factor family (Leu et al 2001, Lin et al 2002.…”

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

“…In T cells, STAT proteins have been shown to physically and functionally interact with members of the Ets family of transcription factors over composite STAT-Ets DNA elements required for cytokine regulation of target genes (60,76). In hepatocytes, STAT3 was shown to cooperate with HFN1 in mediating the transcriptional response to interleukin 6 during liver regeneration (38).…”