Abstract
BackgroundCytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS) in multiple sclerosis (MS).MethodsWe have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M).ResultsIn two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1) seen at 6 hours with microarray.ConclusionEach of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter signaling in glia.
Highlights
Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS) in multiple sclerosis (MS)
Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter signaling in glia
Based on the premise that some of the earliest changes in the pathogenesis of MS lesions would be found in normal appearing white matter (NAWM), where infiltration of immune cells is much less prominent [7,8], Graumann and colleagues [9] analyzed genomic changes in NAWM from patients with secondary progressive MS (SPMS), and found evidence for changes characteristic of neuroprotective mechanisms initially identified in ischemic preconditioning associated with hypoxic insult
Summary
Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS) in multiple sclerosis (MS). Genomic analysis has been applied to investigate changes occurring in the central nervous system (CNS) in multiple sclerosis (MS) These include analyses of acute and chronic active lesions, lesions from patients at different stages of MS, and comparisons of normal appearing white matter (NAWM) and normal appearing gray matter (NAGM). Mahad, et al [12] found decreased expression of mitochondrial Complex IV cytochrome oxidase subunits COX I and COX IV in type III MS lesions, suggesting that the hypoxia-like damage in this type of lesion may result from mitochondrial dysfunction These findings suggest that a wide range of metabolic changes occur in both neurons and glia throughout the MS brain, independent of the local presence of systemic inflammatory cells, and that secretory products of immune cells and activated glia may play central roles in the pathogenesis of and protection from both white matter and gray matter damage in MS
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