Identification of glucocorticoid-induced leucine zipper as a key regulator of tumor cell proliferation in epithelial ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Little is known about the molecules that contribute to tumor progression of epithelial ovarian cancer (EOC), currently a leading cause of mortality from gynecological malignancies. Glucocorticoid-Induced Leucine Zipper (GILZ), an intracellular protein widely expressed in immune tissues, has been reported in epithelial tissues and controls some of key signaling pathways involved in tumorigenesis. However, there has been no report on GILZ in EOC up to now. The objectives of the current study were to examine the expression of GILZ in EOC and its effect on tumor cell proliferation.</p> <p>Results</p> <p>GILZ expression was measured by immunohistochemical staining in tissue sections from 3 normal ovaries, 7 benign EOC and 50 invasive EOC. GILZ was not detected on the surface epithelium of normal ovaries and benign tumors. In contrast, it was expressed in the cytoplasm of tumor cells in 80% EOC specimens. GILZ immunostaining scores correlated positively to the proliferation marker Ki-67 (Spearman test in univariate analysis, <it>P </it>< 0.00001, r = 0.56). They were also higher in tumor cells containing large amounts of phosphorylated protein kinase B (p-AKT) (unpaired t test, <it>P </it>< 0.0001). To assess the effect of GILZ on proliferation and AKT activation, we used the BG-1 cell line derived from ovarian tumor cells as a cellular model. GILZ expression was either enhanced by stable transfection or decreased by the use of small interfering (si) RNA targeting GILZ. We found that GILZ increased cell proliferation, phospho-AKT cellular content and AKT kinase activity. Further, GILZ upregulated cyclin D1 and phosphorylated retinoblastoma (p-Rb), downregulated cyclin-dependent kinase inhibitor p21, and promoted the entry into S phase of cell cycle.</p> <p>Conclusion</p> <p>The present study is the first to identify GILZ as a molecule produced by ovarian cancer cells that promotes cell cycle progression and proliferation. Our findings clearly indicate that GILZ activates AKT, a crucial signaling molecule in tumorigenesis. GILZ thus appears as a potential key molecule in EOC.</p

Impact du règlement REACH sur les industries pharmaceutiques et cosmétiques

Le règlement REACH a été voté afin d'harmoniser les procédures d'évaluation des substances chimiques dans l'Union Européenne. Son innovation consiste à reporter la charge de la preuve de l'innocuité d'une substance à l'industriel qui la commercialise. REACH introduit de nouvelles notions telles que l'enregistrement, l'autorisation ou la restriction afin d'accroître la protection de la santé humaine et environnementale en augmentant les connaissances sur les propriétés des substances et en substituant celles dites préoccupantes dans une démarche de développement durable. Impact économique, stratégique, ou encouragement de l'innovation en R&D, REACH est un règlement complexe qui va entraîner bien des changements au sein de l'industrie chimique mais également des industries pharmaceutiques ou cosmétiques qui utilisent ces substances, malgré les réglementations déjà en vigueur dans ces domaines.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Why the Immune System Should Be Concerned by Nanomaterials?

Particles possess huge specific surface area and therefore nanomaterials exhibit unique characteristics, such as special physical properties and chemical hyper-reactivity, which make them particularly attractive but also raise numerous questions concerning their safety. Interactions of nanomaterials with the immune system can potentially lead to immunosuppression, hypersensitivity (allergy), immunogenicity and autoimmunity, involving both innate and adaptive immune responses. Inherent physical and chemical NP characteristics may influence their immunotoxicity, i.e., the adverse effects that can result from exposure. This review will focus on the possible interaction of nanomaterials including protein aggregates with the innate immune system with specific emphasis on antigen-presenting cells, i.e., dendritic cells, macrophages and monocytes

Les protéines de la famille TSC-22D

Les protéines TSC-22D (TGF-β-stimulated clone-22 domain) forment une famille comportant 18 membres à ce jour. Parmi ceux-ci, la protéine GILZ (glucocorticoid-induced leucine zipper), qui possède un rôle de médiateur des effets anti-inflammatoires des glucocorticoïdes et de régulateur de l’inflammation, fait l’objet d’un nombre croissant d’études. TSC-22, quant à elle, apparaît comme un modulateur de l’apoptose et un gène suppresseur de tumeur. Fortement homologues, GILZ et TSC-22 partagent deux domaines très conservés appelés leucine zipper et TSC-box. Les fonctions associées à ces protéines suggèrent un rôle essentiel pour cette famille dans l’homéostasie cellulaire et la régulation du système immunitaire

Human dendritic cell maturation induced by amorphous silica nanoparticles is Syk-dependent and triggered by lipid raft aggregation

Abstract Background Synthetic amorphous silica nanoparticles (SAS-NPs) are widely employed in pharmaceutics, cosmetics, food and concretes. Workers and the general population are exposed daily via diverse routes of exposure. SAS-NPs are generally recognized as safe (GRAS) by the Food and Drug Administration, but because of their nanoscale size and extensive uses, a better assessment of their immunotoxicity is required. In the presence of immune “danger signals”, dendritic cells (DCs) undergo a maturation process resulting in their migration to regional lymph nodes where they activate naive T-cells. We have previously shown that fumed silica pyrogenic SAS-NPs promote the two first steps of the adaptative immune response by triggering DC maturation and T-lymphocyte response, suggesting that SAS-NPs could behave as immune “danger signals”. The present work aims to identify the mechanism and the signalling pathways involved in DC phenotype modifications provoked by pyrogenic SAS-NPs. As a pivotal intracellular signalling molecule whose phosphorylation is associated with DC maturation, we hypothesized that Spleen tyrosine kinase (Syk) may play a central role in SAS-NPs-induced DC response. Results In human monocyte-derived dendritic cells (moDCs) exposed to SAS-NPs, Syk inhibition prevented the induction of CD83 and CD86 marker expression. A significant decrease in T-cell proliferation and IFN-γ, IL-17F and IL-9 production was found in an allogeneic moDC:T-cell co-culture model. These results suggested that the activation of Syk was necessary for optimal co-stimulation of T-cells. Moreover, Syk phosphorylation, observed 30 min after SAS-NP exposure, occurred upstream of the c-Jun N-terminal kinase (JNK) Mitogen-activated protein kinases (MAPK) and was elicited by the Src family of protein tyrosine kinases. Our results also showed for the first time that SAS-NPs provoked aggregation of lipid rafts in moDCs and that MβCD-mediated raft destabilisation altered Syk activation. Conclusions We showed that SAS-NPs could act as an immune danger signal in DCs through a Syk-dependent pathway. Our findings revealed an original mechanism whereby the interaction of SAS-NPs with DC membranes promoted aggregation of lipid rafts, leading to a Src kinase-initiated activation loop triggering Syk activation and functional DC maturation

Synthetic Amorphous Silica Nanoparticles Promote Human Dendritic Cell Maturation and CD4+ T-Lymphocyte Activation

International audienceInnate immune cells such as dendritic cells (DCs) sense and engulf nanomaterials potentially leading to an adverse immune response. Indeed, as described for combustion-derived particles, nanomaterials could be sensed as danger signals, enabling DCs to undergo a maturation process, migrate to regional lymph nodes and activate naive T lymphocytes. Synthetic amorphous silica nanoparticles (SAS-NPs) are widely used as food additives, cosmetics, and construction materials. This work aimed to evaluate in vitro the effects of manufactured SAS-NPs, produced by thermal or wet routes, on human DCs functions and T-cell activation. Human monocyte-derived DCs (moDCs) were exposed for 16 h to 3 endotoxin-free test materials: fumed silica NPs from Sigma-Aldrich (no. S5505) or the JRC Nanomaterial Repository (NM-202) and colloidal LudoxTMA NPs. Cell viability, phenotypical changes, cytokines production, internalization, and allogeneic CD4+ T-cells proliferation were evaluated. Our results showed that all SAS-NPs significantly upregulated the surface expression of CD86 and CD83 activation markers. Secretions of pro-inflammatory cytokines (CXCL-8 and CXCL-12) were significantly enhanced in a dose-dependent manner in the moDCs culture supernatants by all SAS-NPs tested. In an allogeneic coculture, fumed silica-activated moDCs significantly increased T-lymphocyte proliferation at all T-cell: DC ratios compared with unloaded moDCs. Moreover, analysis of coculture supernatants regarding the production of T-cell-derived cytokines showed a significant increase of IL-9 and IL-17A and F, as well as an upregulation of IL-5, consistent with the pro-inflammatory phenotype of treated moDCs. Taken together, these results suggest that SAS-NPs could induce functional moDCs maturation and play a role in the immunization process against environmental antigens