Simvastatin inhibits interferon-γ-induced MHC class II up-regulation in cultured astrocytes

Based on their potent anti-inflammatory properties and a preliminary clinical trial, statins (HMG-CoA reductase inhibitors) are being studied as possible candidates for multiple sclerosis (MS) therapy. The pathogenesis of MS is unclear. One theory suggests that the development of autoimmune lesions in the central nervous system may be due to a failure of endogenous inhibitory control of MHC class II expression on astrocytes, allowing these cells to adapt an interferon (IFN)-γ-induced antigen presenting phenotype. By using immunocytochemistry in cultured astrocytes derived from newborn Wistar rats we found that simvastatin at nanomolar concentrations inhibited, in a dose-response fashion, up to 70% of IFN-γ-induced MHC class II expression. This effect was reversed by the HMG-CoA reductase product mevalonate. Suppression of the antigen presenting function of astrocytes might contribute to the beneficial effects of statins in MS

Insulinlike Growth Factor-Binding Protein-1 Improves Vascular Endothelial Repair in Male Mice in the Setting of Insulin Resistance

Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor–binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance

Insulin-like growth factor system in glial cells

As an intrinsic part of the normal operative CNS, glial cells perform a plethora of functions. They comprise a large fraction of the brainís cell population and their presence provides structure support, helping to mold physiologically functional components, such as the blood-brain barrier and myelin sheaths. Glial expression of factors influencing cellular growth, differentiation and survival, together with factors regulating immunological processes are of great importance and overwhelmingly complex. Elucidating mechanisms involved in governing regulation of such processes is important for understanding cellular events and crucial in the case of pathologies, where there is often urgency for therapeutic interventions. The pathological situation known as multiple sclerosis is a demyelinating disease of the CNS. Therapeutic strategies attempt to intervene in a variety of mechanisms associated with MS. One possible strategy involves the application of growth factors aimed at repairing damage caused by immune invasion and replenishing precursor cell populations. Because IGF-1 has the potential to stimulate myelin production and proliferation of oligodendrocyte precursor cells this factor provides a promising tool in treating demyelinating diseases. However, the complex nature of IGF-1 regulation is not completely understood. In order to design a rational approach to obtain the desired effects, our knowledge of the IGF-system in the CNS must be extended. This thesis describes studies, aimed at elucidating the involvement of IGF and the regulatory IGFBPs on glial cell functions, with emphasis on astrocytes.

Progesterone and dexamethasone differentially regulate the IGF-system in glial cells

IGF-1 is an important factor for myelin synthesis and hence possesses therapeutic potential in treating demyelinating disease such as multiple sclerosis. However, IGF-1 poorly crosses the blood-brain barrier. In this study, we investigated the effects of the sex steroid progesterone and the glucocorticoid dexamethasone on regulation of the IGF-system in glial cells. By means of quantitative PCR analysis, we demonstrate that progesterone upregulates IGF-1, the type 1 IGF receptor and IGFBP-2 in primary rat astrocytes and both IGF-1 and IGFBP-6 in OLN-93 oligodendroglial progenitor cells. In contrast, dexamethasone showed a negative effect on expression of IGF-1, the type I IGF receptor and the respective IGF binding proteins in both cell types. In oligodendrocytes, the differentiation marker CNPase was positively regulated by progesterone and negatively regulated by dexamethasone. Further, oligodendroglial cell migration was enhanced approximately 4-fold by progesterone. This study implicates progesterone as a positive regulator of IGF-system in glial cells and demonstrates a further biological function of progesterone in oligodendrocyte biology, namely stimulation of progenitor cell migration. Dexamethasone, on the other hand. is a negative regulator of the IGF-system in glial cells. (C) 2009 Elsevier Ireland Ltd. All rights reserved