Gene transcription in hepatocytes during the acute phase of a systemic inflammation: from transcription factors to target genes

Abstract

During an acute, systemic inflammation, the liver is triggered by blood-borne pro-inflammatory cytokines such as Tumor Necrosis Factor alpha, Interleukin-1beta and Interleukin-6. The end result is an up- or down-regulated synthesis and/or activation of liver-enriched transcription factors that in turn regulate many target genes coding for resident or secreted acute phase proteins. In this review, various classifications of these acute phase proteins are presented. Major inflammation-driven changes in the synthesis and/or activity of the hepatic transcription factors are illustrated. Some of their up- or down-regulated target genes are used as paradigms of the various transcriptional mechanisms that take place on gene promoters during an acute, systemic inflammation. Finally, further specific features of inflammation-associated gene transcription in liver from acute phase onset to resolution are provided.

Altered gene expression in acute systemic inflammation detected by complete coverage of the human liver transcriptome

“…5B) code for proinflammatory cytokines (e.g., interleukin [IL]-8), TFs (e.g., CCAAT-enhancer binding protein [C/EBP]-␤), and several complement components and APPs (e.g., CRP, SAA 1, orosomucoid) that are AP regulated. 14,30 Some other gene products have not been previously associated with AP (names written in blue block letters in Fig. 5B) and extend the number of AP-regulated anti-pathogen response proteins.…”

“…Other mRNAs correspond to factors involved in transcriptional repression (prospero-related homeobox 1, RPB5-mediating protein, rev-Erb-related NR1D2, Ets variant Etv3) or chromatin rearrangement (MSL3-like1, DNA helicase type 2, structure-specific recognition protein 1). It is noteworthy that none of the mRNAs for transcriptional activators that are known to be up-regulated by the AP in liver, namely, NF B, C/EBP-␤ and C/EBP-␦, and STAT-3, 14 was found in this list. These mRNAs are up-regulated only after latent NF B, C/EBP-␤, and STAT-3 molecules that preexist in the cytosol of quiescent hepatocytes have been rapidly imported to the nucleus at the onset of AP.…”

“…In the liver, these TFs mostly comprise nuclear factor B (NF B), activating protein-1, signal transducer and activator of transcription-3 (STAT-3), and some members of the C/EBP family. 14 The occurrence of potential binding sites for one or more of these factors in the promoters of some of the 154 genes was compared with their occurence in a random set of control genes transcribed at least in the liver. The results detailed in our supplementary Table s3 point to a significantly higher number of potential sites for NF B and activating protein-1 in the AP-regulated genes compared with the control gene set.…”

“…This correlation value allowed us to rank the resulting series of 134 newly identified mRNAs as novel AP markers and, in this respect, some of them outperformed some wellknown markers. Remarkably, haptoglobin, ALB, and TSF are classically used as AP markers 14,15 and they participated in the initial assignment of an AP score to our patients. Haptoglobin, ALB, and TSF mRNAs were also listed in our preliminary selection of 772 genes but they did not pass our final selection for genes whose mRNA abundance correlates with the AP score.…”

“…11,12 In addition, the acute phase (AP) of a systemic inflammation up-regulates or down-regulates many liver-expressed genes involved in innate immunity and coding, for instance, for the positive or negative plasma acute phase proteins (APP). [13][14][15][16] However, a global view of the AP-induced changes in the liver transcriptome has not yet been obtained in humans in vivo. We report the development of an array based on selected human complementary DNA (cDNA) probes that correspond to approximately 10,000 nonredundant genes and specifically cover the liver transcriptome.…”