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

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.

Survival of Escherichia coli during long-term starvation: effects of aeration, NaCl, and the rpoS and osmC gene products.

The survival of Escherichia coli was investigated during long-term starvation in rich media. In aerated cultures, E. coli lost the ability to form colonies earlier in NaCl-free Luria broth than in LB medium containing NaCl. Improved survival at low aeration and the sensitivity to hydrogen peroxide in aging cultures indicated a major role for oxidative stress in cell mortality. Mutants in rpoS, lacking the sigmaS subunit of RNA polymerase, showed altered survival in salt-containing media. However, in the absence of NaCl, although these mutants exhibited a massive loss of viability during the first 2 days, this was followed by a stabilization of the number of survivors. The starved culture contained survivors until at least day 9, long after a wild-type strain had completely lost viability. This peculiar behavior suggests that, in rich media of low osmotic pressure, sigmaS helps in short-term survival but hampers long-term survival. Mutants in osmC, a member of the rpoS regulon, also exhibited reduced survival and increased sensitivity to oxidative stress. The biochemical function of the envelope protein OsmC remains unknown, but present data indicated that it participates, directly or indirectly, in the defense against oxidative compounds.

Positive and negative elements modulate the promoter of the human liver-specific alpha2-HS-glycoprotein gene.

The human alpha2-HS-glycoprotein (AHSG) and the 63-kDa rat phosphoprotein (pp63) are homologous plasma proteins that belong to the fetuin family. AHSG and pp63 are involved in important functions such as inhibition of insulin receptor tyrosine kinase activity, inhibition of protease activities, and regulation of calcium metabolism and osteogenesis. Studies of the AHSG proximal promoter performed in vitro in rat and human cells indicate that several NF-1 and C/EBP binding sites exert a positive effect on its transcriptional activity. However, until now, no distal elements have been examined in this gene, in either species. We report that the human AHSG gene promoter acts in a liver-specific manner and is further controlled by three distal, 5'-flanking elements. The negative elements III and I are, respectively, located 5' and 3' of the positive element II. All three elements require the natural context of the human AHSG gene to fully exert their negative or positive effect. Element I harbours a single binding site for NF-1. This nuclear factor thus appears to be able to up- or downregulate the AHSG gene depending on the site it binds to. Elements I, II and possibly III are absent in the rodent Ahsg gene encoding pp63.

Structural and functional analysis of the 5'-transcription control region for the human alpha2-HS glycoprotein gene.

The human alpha2-HS glycoprotein (A2HS) and rat phosphoprotein of Mr 63000 (pp63) are homologous plasma proteins and members of the fetuin superfamily. A2HS is involved in important functions such as inhibition of the tyrosine kinase activity of the insulin receptor, regulation of calcium metabolism and osteogenesis as well as protease inhibitory activity. We report an analysis of the 5' transcription control region (4 kb) of the A2HS gene. Its most proximal 300 nt display a very potent transcriptional activity. The latter is likely accounted for by C/EBP and NF1 binding sites that are conserved from the human A2HS gene to the rat pp63 gene. In contrast, these human and rat genes appear to largely diverge beyond their proximal promoter.

The Rhizobium meliloti PII protein, which controls bacterial nitrogen metabolism, affects alfalfa nodule development.

Symbiotic nitrogen fixation involves the development of specialized organs called nodules within which plant photosynthates are exchanged for combined nitrogen of bacterial origin. To determine the importance of bacterial nitrogen metabolism in symbiosis, we have characterized a key regulator of this metabolism in Rhizobium meliloti, the uridylylatable P(II) protein encoded by glnB. We have constructed both a glnB null mutant and a point mutant making nonuridylylatable P(II). In free-living conditions, P(II) is required for expression of the ntrC-dependent gene glnII and for adenylylation of glutamine synthetase I. P(II) is also required for efficient infection of alfalfa but not for expression of nitrogenase. However alfalfa plants inoculated with either glnB mutant are nitrogen-starved in the absence of added combined nitrogen. We hypothesize that P(II) controls expression or activity of a bacteroid ammonium transporter required for a functional nitrogen-fixing symbiosis. Therefore, the P(II) protein affects both Rhizobium nitrogen metabolism and alfalfa nodule development.