Prion infections of the central nervous system (CNS) are characterised by a reactive gliosis and the subsequent degeneration of neuronal tissue. The activation of glial cells, which precedes neuronal death, is likely to be initially caused by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrP(res)) of the prion protein (PrP) in the brain. Cytokines and chemokines released by PrP(res)-activated glia cells may contribute directly or indirectly to the disease development by enhancement and generalisation of the gliosis and via cytotoxicity for neurons. However, the actual role of prion-induced glia activation and subsequent cytokine/chemokine secretion in disease development is still far from clear. In the present work, we review our present knowledge concerning the functional biology of cytokines and chemokines in prion infections of the CNS.
"These changes are associated with the deposits of imperfectly folded proteinase K-resistant isoforms (termed PrP(res)) of the prion protein (PrP) in the brain. Cytokines and chemokines released by PrP(res)-activated glial cells may contribute directly or indirectly to development of the disease by enhancement and generalisation of the gliosis and via neuronal cytotoxicity (Eikelenboom et al., 2002; Burwinkel et al., 2004). Since the synthetic prion peptide PrP 106–126 shares many properties with PrP it is widely used for in vitro studies. "
[Show abstract][Hide abstract] ABSTRACT: Invasion of the nervous system and neuronal spread of infection are critical, but poorly understood steps in the pathogenesis of prion diseases. We have thus analyzed the internalization and signal transduction of the neurotoxic fragment of the prion protein PrP(106-126) in the rat neuroblastoma cell line B104 by fluorescence microscopy and quantification by ELISA and in primary neuronal cells from mice. Phospholipase D (PLD) is known to be an enzyme involved in the regulation of secretion, endocytosis and receptor signalling. We determined the PLD activity using a transphosphatidylation assay and could show that PLD is involved in PrP(106-126) internalization. The determination of receptor activity via quantification of ERK1/2 phosphorylation and cAMP level measurement verified the PrP(106-126)-induced signal transduction in B104 cells and primary neuronal cells. PrP(106-126)-induced a decrease in cAMP level in neuronal cells. These studies indicate the involvement of PLD in PrP(106-126)-endocytosis and mediated cellular signalling by an unidentified inhibitory G-protein-coupled receptor and may allow the development of therapeutic agents interfering with prion uptake and/or PLD function using PLD as a possible pharmaceutical target.
Annals of anatomy = Anatomischer Anzeiger: official organ of the Anatomische Gesellschaft 08/2009; 191(5):459-68. DOI:10.1016/j.aanat.2009.06.003 · 1.48 Impact Factor
"), as those shown in Tables 4 and 6. Glial activation and the production of proinflammatory chemokines and cytokines have been shown to be associated with many central nervous system (CNS) diseases, such as bacterial or viral infection, multiple sclerosis, prion infection, Parkinson's disease, Alzheimer's disease and ischemia (Burwinkel et al., 2004; Choi et al., 2005; Meda et al., 2001). This association is in complete agreement with our findings that proinflammatory chemokines and cytokines are up-regulated and that the IFN-g signaling pathway may be activated by Mn 2+ in astrocytes. "
[Show abstract][Hide abstract] ABSTRACT: Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes at a genome-wide level, by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated, whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. Consistent with the increased expression of proinflammatory factors, analysis of common regulators revealed that 16 targets known to be positively affected by the interferon-gamma signaling pathway were up-regulated by Mn(2+). In addition, 68 genes were found to be similarly up- or down-regulated by both Mn(2+) and hypoxia. These results from genomic analysis are further supported by data from real-time RT-PCR, Western blotting, flow cytometric and toxicological analyses. Together, these analyses show that Mn(2+) selectively affects cell cycle progression, the expression of hypoxia-responsive genes, and the expression of proinflammatory factors in primary human astrocytes. These results provide important insights into the molecular mechanisms underlying Mn neurotoxicity.
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