IFN-β-1a has been used over the past 15 years as a primary therapy for relapsing-remitting multiple sclerosis (MS). However, the immunomodulatory mechanisms that provide a therapeutic effect against this CNS inflammatory disease are not yet completely elucidated. The effect of IFN-β-1a on Th17 cells, which play a critical role in the development of the autoimmune response, has not been extensively studied in humans. We have investigated the effect of IFN-β-1a on dendritic cells (DCs) and naive CD4+CD45RA+ T cells derived from untreated MS patients and healthy controls in the context of Th17 cell differentiation. We report that IFN-β-1a treatment down-regulated the expression of IL-1β and IL-23p19 in DCs, whereas it induced the gene expression of IL-12p35 and IL-27p28. We propose that IFN-β-1a-mediated up-regulation of the suppressor of cytokine signaling 3 expression, induced via STAT3 phosphorylation, mediates IL-1β and IL-23 down-regulation, while IFN-β-1a-induced STAT1 phosphorylation induces IL-27p28 expression. CD4+CD45RA+ naive T cells cocultured with supernatants from IFN-β-1a-treated DCs exhibited decreased gene expression of the Th17 cell markers retinoic acid-related orphan nuclear hormone receptor c (RORc), IL-17A, and IL-23R. A direct IFN-β-1a treatment of CD45RA+ T cells cultured in Th17-polarizing conditions also down-regulated RORc, IL-17A, and IL-23R, but up-regulated IL-10 gene expression. Studies of the mechanisms involved in the Th17 cell differentiation suggest that IFN-β-1a inhibits IL-17 and induces IL-10 secretion via activated STAT1 and STAT3, respectively. IFN-β’s suppression of Th17 cell differentiation may represent its most relevant mechanism of selective suppression of the autoimmune response in MS.

Statins, extensively used as cholesterol-lowering agents, have recently been identified as immunomodulatory agents. This study investigated the statins’ mechanisms that target the autoimmune response in humans, and evaluated their therapeutic potential in multiple sclerosis. Our results demonstrated statin-mediated increases in suppressor of cytokine secretion (SOCS) 3 and suppressor of cytokine secretion 7, which negatively regulate the STAT/JAK signal transduction pathway and IL-6 and IL-23 gene expression in monocytes. Simvastatin also induced IFN-γ, IL-4, and IL-27 production in monocytes, which together inhibited IL-17 transcription and secretion in CD4+ T cells. IL-17-producing CD4+ cells, referred to as Th17 cells, have recently been found to play a central role in the development of autoimmune diseases. Furthermore, simvastatin directly inhibited the expression of retinoic acid-related orphan nuclear hormone receptor C, a transcription factor that controls IL-17 production in CD4+ T cells. This effect was reversed by mevalonic acid, a downstream metabolite of 3-hydroxy-3-methylglutaryl CoA reductase, confirming that simvastatin’s specific effect is through the inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase. These results provide evidence for the novel immunomodulatory mechanisms of statins, which selectively target the regulation of cytokine transcription involved in the development of the human autoimmune response. Based on the described immunomodulatory mechanisms, good safety profile and oral bioavailability, statins represent a promising therapeutic approach for multiple sclerosis and other chronic inflammatory diseases.

The role of cytokines in the pathogenesis of cardiovascular disease is increasingly evident since the identification of immune/inflammatory mechanisms in atherosclerosis and heart failure. In this review, we describe how innate and adaptive immune cascades trigger the release of cytokines and chemokines, resulting in the initiation and progression of atherosclerosis. We discuss how cytokines have direct and indirect effects on myocardial function. These include myocardial depressant effects of nitric oxide (NO) synthase-generated NO, as well as the biochemical effects of cytokine-stimulated arachidonic acid metabolites on cardiomyocytes. Cytokine influences on myocardial function are time-, concentration-, and subtype-specific. We provide a comprehensive review of these cytokine-mediated immune and inflammatory cascades implicated in the most common forms of cardiovascular disease.

Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the β2 integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-α, GM-CSF, and IL-3 mRNA, as well as a chimeric β-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA 3′-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-α ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF-α or IFN-γ transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.

The scAAV viral vector provides prolonged and safe transduction in the trabecular meshwork of rats and monkeys. The stable expression and safe properties of this vector could facilitate the development of trabecular meshwork drugs for gene therapy for glaucoma.