A synthetic self-assembled fibrillar nanovaccine decorated with an antigenic determinant from the Chikungunya virus elicits a robust immune response.

Glycogen synthase kinase 3 (GSK-3) is associated with several cellular systems, including immune response. Lithium, a widely used pharmacological treatment for bipolar disorder, is a GSK-3 inhibitor. GSK-3α is the predominant isoform in human neutrophils. In this study, we examined the effect of GSK-3 inhibition on the production of TNF-α by neutrophils. In the murine air pouch model of inflammation, lithium chloride (LiCl) amplified TNF-α release. In lipopolysaccharide-stimulated human neutrophils, GSK-3 inhibitors mimicked the effect of LiCl, each potentiating TNF-α release after 4 h, in a concentration-dependent fashion, by up to a 3-fold increase (ED50 of 1 mM for lithium). LiCl had no significant effect on cell viability. A positive association was revealed between GSK-3 inhibition and prolonged activation of the p38/MNK1/eIF4E pathway of mRNA translation. Using lysine and arginine labeled with stable heavy isotopes followed by quantitative mass spectrometry, we determined that GSK-3 inhibition markedly increases (by more than 3-fold) de novo TNF-α protein synthesis. Our findings shed light on a novel mechanism of control of TNF-α expression in neutrophils with GSK-3 regulating mRNA translation and raise the possibility that lithium could be having a hitherto unforeseen effect on inflammatory diseases.

The murine dorsal air pouch model is a valuable tool for studying acute peripheral inflammatory reactions. We used this model to study the effect of diet on the onset of acute inflammation. Mice were fed a normal or a high-fat diet (HFD) for 5 weeks. Air pouches were raised and injected with non-stimulating (saline) or stimulating solution (saline containing lipopolysaccharides). After 4 h, leukocytes in the pouch fluid were enumerated, sorted and their viability measured. Cytokine/chemokine levels in the cell-free fluid were measured using a cytometric bead assay. Gene expression level was measured in leukocytes and in lining tissues using comparative real-time PCR. Leukocyte migration and cytokine/chemokine secretion were decreased substantially in mice fed the HFD. In contrast, leptin levels were elevated. Gene expression profiles in leukocytes recovered from the pouch and in the pouch-lining tissue (believed to have an important role in the initiation of granulocyte recruitment) were depressed. Genes encoding CC and CXC family chemokines were among the most negatively affected. These results suggest that a HFD can alter peripheral tissue activation as well as leukocyte recruitment and response, thereby affecting the development of an effective local immune response, which could have deleterious consequences.

Introduction Expressed in response to injury or infection, tumour necrosis factoralpha (TNF-α) is a highly potent mediator of inflammation. Controlled expression of TNF-α is crucial, since overexpression can lead to autoimmune disease and tissue damage. TNF-α expression is regulated at different levels, including transcription, mRNA turnover and translation. Many reviews have focused on the signalling pathways that mediate cellular responses following TNF-α receptor engagement. In this article, we focus on an aspect that shows promise for pharmaceutical intervention, namely intracellular mechanisms regulating production of TNF-α in immune cells, especially post-transcriptional checkpoints. We discuss the roles of adenosineuridine-rich-element-binding proteins, micro-RNA and MAP kinase in the post-transcriptional regulation of TNF-α mRNA activity and their relevance to the physiopathology of rheumatoid arthritis. Conclusion A better understanding of the intracellular proteins and signalling pathways that regulate TNF-α biosynthesis is crucial to the development of novel anti-TNF-based therapies for rheumatoid arthritis patients.