The cytokine macrophage migration inhibitory factor plays a central role in inflammation, cell proliferation and tumorigenesis. Moreover, macrophage migration inhibitory factor levels correlate with ...tumor aggressiveness and metastatic potential. Histone deacetylase inhibitors are potent antitumor agents recently introduced in the clinic. Therefore, we hypothesized that macrophage migration inhibitory factor would represent a target of histone deacetylase inhibitors. Confirming our hypothesis, we report that histone deacetylase inhibitors of various chemical classes strongly inhibited macrophage migration inhibitory factor expression in a broad range of cell lines, in primary cells and
in vivo. Nuclear run on, transient transfection with macrophage migration inhibitory factor promoter reporter constructs and transduction with macrophage migration inhibitory factor expressing adenovirus demonstrated that trichostatin A (a prototypical histone deacetylase inhibitor) inhibited endogenous, but not episomal,
MIF gene transcription. Interestingly, trichostatin A induced a local and specific deacetylation of macrophage migration inhibitory factor promoter-associated H3 and H4 histones which did not affect chromatin accessibility but was associated with an impaired recruitment of RNA polymerase II and Sp1 and CREB transcription factors required for basal
MIF gene transcription. Altogether, this study describes a new molecular mechanism by which histone deacetylase inhibitors inhibit
MIF gene expression, and suggests that macrophage migration inhibitory factor inhibition by histone deacetylase inhibitors may contribute to the antitumorigenic effects of histone deacetylase inhibitors.
Toll-like receptor 4 (TLR4) is involved in the sensing of lipopolysaccharide and, therefore, plays a central role in innate immune responses to gram-negative bacteria. Interestingly, TLR4 expression ...occurs within the kidney. We have previously demonstrated that angiotensin II (ANG II) upregulates TLR4 expression on mesangial cells. However, the factors controlling transcriptional activation of the Tlr4 gene in mesangial cells are not known, and the specificity of this response for other renal cells is unclear.
Cultured murine proximal tubular cells (mouse cortical tubule cell line; MCT cells), murine mesangial cells (MMCs), and murine podocytes were treated with ANG II. The expression of ANG II receptor mRNA and TLR4 mRNA and protein was determined by polymerase chain reaction and Western blotting. The transcriptional activity of wild-type and mutant mouse TLR4 promoter reporter constructs was determined upon transient transfection of the three cell types.
Although MMCs, podocytes, and syngeneic proximal MCT cells similarly expressed ANG II receptors, ANG II stimulated TLR4 mRNA and protein expression in MMCs and podocytes only. A mouse TLR4 promoter construct (-518/+129), previously shown to contain all important transcriptional regulatory elements in various cell types, was activated by ANG II in MMCs and podocytes, but not in MCT cells. Mutation of a proximal PU.1-binding consensus site or an AP1 site abolished ANG-II-mediated transcriptional activation of the TLR4 promoter. Finally, basal transcription of the Tlr4 gene depended in all three cell lines on an intact AP1 site and additionally on the proximal PU.1 site in MMCs.
ANG II stimulates TLR4 transcription through AP1 and PU.1 sites in a cell-specific manner. Since the intrarenal ANG II concentrations are enhanced in many pathophysiological situations, ANG-II-stimulated transcription of TLR4 on MMCs and podocytes may contribute to renal inflammation.
The glucocorticoid-induced leucine zipper (Tsc22d3-2) is a widely expressed dexamethasone-induced transcript that has been proposed to be important in immunity, adipogenesis, and renal sodium ...handling based on in vitro studies. To address its function in vivo, we have used Cre/loxP technology to generate mice deficient for Tsc22d3-2. Male knockout mice were viable but surprisingly did not show any major deficiencies in immunological processes or inflammatory responses. Tsc22d3-2 knockout mice adapted to a sodium-deprived diet and to water deprivation conditions but developed a subtle deficiency in renal sodium and water handling. Moreover, the affected animals developed a mild metabolic phenotype evident by a reduction in weight from 6 months of age, mild hyperinsulinemia, and resistance to a high-fat diet. Tsc22d3-2-deficient males were infertile and exhibited severe testis dysplasia from postnatal d 10 onward with increases in apoptotic cells within seminiferous tubules, an increased number of Leydig cells, and significantly elevated FSH and testosterone levels. Thus, our analysis of the Tsc22d3-2-deficient mice demonstrated a previously uncharacterized function of glucocorticoid-induced leucine zipper protein in testis development.
Il y a, spécifiquement, une affaire Mallarmé.H. Meschonnic, « Oralité, clarté de Mallarmé », Europe, janvier-février 1998. Comme la matière ne saurait être envisagée sans l’antimatière, les sciences ...humaines, elles aussi, bien souvent, soudés à leurs objets, génèrent leurs anti-objets. C’est le jeu bien connu de « l’action » et de « la réaction », cher à Jean Starobinski. Depuis quelques années, l’histoire des idées considère l’autre moitié de l’orange quand l’histoire de la réception se penc...
•We have developed the first induced large animal glioma model.•Ciclosporine was used for the immunomodulation.•The time to develop a tumor is short and reproducible with U87 MG cells, allowing ...preclinical studies.•Pig and human brains are macroscopically similar, providing realistic condition for convection enhanced-delivery protocol.
The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood–brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use.
Angiotensin II (AngII) mediates proinflammatory properties by activating NF-kappaB transcription factor nuclear translocation and inducing the expression of chemokines. For examination of whether ...AngII modulates the expression of Toll-like receptor 4 (TLR4), a key element of the innate immune system that senses LPS, mouse mesangial cells (MMC) were treated with AngII. AngII upregulated TLR4 mRNA and protein in MMC, and this effect was mediated through AngII type 1 receptors. Reporter gene experiments indicate that an activating protein-1 (AP-1) as well as an E-26 specific sequence (Ets) binding site in the TLR4 promoter are responsible for the AngII-stimulated transcriptional activity of the TLR4 gene. Preincubation of MMC with AngII enhanced LPS-induced NF-kappaB activation and chemokine expression. Immunohistochemical analyses revealed that double-transgenic rats that overexpressed human renin and angiotensinogen expressed higher levels of glomerular TLR4 compared with normal Sprague-Dawley rats. In vivo, infusion with AngII but not with norepinephrine into rats for 7 d also enhanced glomerular NF-kappaB activation after systemic application of LPS, suggesting that the effects are independent of concomitantly induced hypertension. Together, these observations suggest that AngII leads to an activation of the innate immune system by a novel mechanism involving the upregulation of TLR4. Our data contribute to a better understanding of how exogenous infections may trigger renal autoimmune processes, particularly in pathophysiologic situations with high renal AngII concentrations. Because TLR4 binds endogenous ligands (e.g., extracellular matrix components) in addition to microbial products, AngII-mediated upregulation of TLR4 also could be relevant for the development of inflammation in many noninfectious renal diseases.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic beta-cells, liver, skeletal muscle, and adipocytes. This study ...investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIF-/-) mice. Compared with wild-type (WT) mice, MIF-/- mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIF-/- mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIF-/- mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIF-/- mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIF-/- mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIF-/- mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIF-/- mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis.
Tiré de dix années d’oubli par Verlaine, rival posthume de Laforgue, salué par Tzara et Breton, Corbière n’est pas seulement le « poète maudit » ni « moderniste » qu’une certaine histoire littéraire ...a construit. Son œuvre, traversée par une puissance de dérision féroce, propose un recommencement du lyrisme à partir d’une esthétique polyphonique qui mêle dissonance antiromantique et consonance primitiviste. Son « ironie lyrique » (Bakhtine) perpétuelle ne peut plus être une quête de soi, mais une quête du vrai qui se fera aussi recueil de voix. Où l’on découvrira un « Maître-philosophe cynique » qui nous apprend à mourir de rire, qui «joue du couteau » contre une certaine tradition, romantique, contre le présent, parnassien, mais aussi contre la domination grapho-centrique, et donc pour l’inscription du corps dans la langue : « Si ce n’est pas vrai - Que je crève ! »
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