Laquinimod dampens IL-1beta signaling and Th17-polarizing capacity of monocytes in patients with MS

OBJECTIVE: To assess the impact of laquinimod treatment on monocytes and to investigate the underlying immunomodulatory mechanisms in MS. METHODS: In this cross-sectional study, we performed in vivo and in vitro analyses of cluster of differentiation (CD14(+)) monocytes isolated from healthy donors (n = 15), untreated (n = 13), and laquinimod-treated patients with MS (n = 14). Their frequency and the expression of surface activation markers were assessed by flow cytometry and the viability by calcein staining. Cytokine concentrations in the supernatants of lipopolysaccharide (LPS)-stimulated monocytes were determined by flow cytometry. The messenger ribonucleic acid (mRNA) expression level of genes involved in cytokine expression was measured by quantitative PCR. The LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-kappaB) activation was determined by the quantification of the phosphorylation level of the p65 subunit. Laquinimod-treated monocytes were cocultured with CD4(+) T cells, and the resulting cytokine production was analyzed by flow cytometry after intracellular cytokine staining. The interleukin (IL)-17A concentration of the supernatant was assessed by ELISA.RESULTS: Laquinimod did not alter the frequency or viability of circulating monocytes, but led to an upregulation of CD86 expression. LPS-stimulated monocytes of laquinimod-treated patients with MS secreted less IL-1beta following a downregulation of IL-1beta gene expression. Phosphorylation levels of the NF-kappaB p65 subunit were reduced after laquinimod treatment, indicating a laquinimod-associated inhibition of the NF-kappaB pathway. T cells primed with laquinimod-treated monocytes differentiated significantly less into IL-17A-producing T helper (Th)-17 cells.CONCLUSIONS: Our findings suggest that inhibited NF-kappaB signaling and downregulation of IL-1beta expression in monocytes contributes to the immunomodulatory effects of laquinimod and that the impairment of Th17 polarization might mediate its disease-modifying activity in MS

Neural Stem Cell Differentiation Is Dictated by Distinct Actions of Nuclear Receptor Corepressors and Histone Deacetylases

Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs). However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs remains unclear. Here, we show by genome-wide analysis that histone deacetylase (HDAC)2 and HDAC3 show overlapping and distinct promoter occupancy at neuronal and oligodendrocyte-related genes in NSCs. The absence of HDAC3, but not HDAC2, initiated a neuronal differentiation pathway in NSCs. The ablation of the corepressor NCOR or HDAC2, in conjunction with T3 treatment, resulted in increased expression of oligodendrocyte genes, revealing a direct HDAC2-mediated repression of Sox8 and Sox10 expression. Interestingly, Sox10 was required also for maintaining the more differentiated state by repression of stem cell programming factors such as Sox2 and Sox9. Distinct and nonredundant actions of NCORs and HDACs are thus critical for control of lineage progression and differentiation programs in neural progenitors

Après le texte

Textes réunis et présentés par Rudolf Mahrer La critique génétique a longtemps considéré que le processus d’élaboration des œuvres prenait fin avec la publication. L’avant-texte était son territoire. L’après-texte relevait d’autres approches. Ce numéro de Genesis interroge cette position en s’autorisant pour la première fois un regard large sur la pratique de la réécriture après publication. Car Andersen, Schopenhauer, Mallarmé, Balzac, Ramuz, Cendrars, Reverdy, Derrida ou Duras ne s’en sont pas laissé compter : chez eux comme chez bien d’autres, le processus créatif n’a pas toujours été arrêté par la première publication (ni même parfois par la deuxième, la troisième…). Les études réunies ici – comme les images ébouriffantes de livres couverts de ratures, ou encore le témoignage d’un réécrivain invétéré : Jean Starobinski – font bien sentir que les cas de réécriture après édition ne se réduisent pas à des « exceptions qui confirment la règle ». Que change-t-on à une œuvre pourtant « finie » et déjà livrée au public ? Et pourquoi changer encore ? Répondre à ces deux questions, de manière singulière (sections « Études ») ou plus générale (section « Enjeux »), conduit à réenvisager les relations entre philologie et génétique, ou entre écriture et publication. Car la mise en circulation du texte ne signe pas la fin de son élaboration, mais transforme les conditions de sa poursuite. Composant avec la première réception de l’œuvre ou les collaborateurs de l’édition, la phase post-éditoriale de la création est sans conteste la plus contrainte. Ce n’est pas le moindre de ses intérêts, le livre n’étant pas un brouillon tout à fait comme les autres