With regard to changes in mitochon drial enzymes, the pattern of changes with Th1 cytokines was quite distinct from that seen with MM cytokines, while Th2 cytokines induced only a few more modest changes. With Th1 cytokines, marked downregulation of the COX VI subunit was seen. this differs from the decrease in the COX IV subunit reported in MS tissue, and may provide a clue to the selleck chemical Regorafenib very earliest changes occurring in mitochondrial function in glia exposed to proinflam matory cytokines, as may the very early downregulation of the 16s mitochondrial ribosomal RNA, which would effect all of the 13 mitochondrial encoded genes. Upregu lation by Th1 of genes for transcription factors such as junB, NF ?B and CREB might be predicted, while the decreases in HNF3 and 4 and the increase in the genes for the fox 1 homolog and jagged 1 by Th1 cytokines in glia have not been previously reported.

Again, the many changes seen in expression of genes for proteasome, ubiq uitin and synuclein proteins with Th1 cytokines might be anticipated, but stand Inhibitors,Modulators,Libraries in contrast to the relatively few changes seen in response to MM and Th2 cytokines. Finally, lipid synthesis and signaling pathways have not been extensively explored Inhibitors,Modulators,Libraries in glia in response to cytokines. most notably, decreases by Th1 at 6 hours in the genes coding for synthesis of galactocerebroside Inhibitors,Modulators,Libraries implicate changes in oligodenroglial function, since the lipid serves as the precursor for sulfatide, shown to be critical for maintaining normal architecture and function at the nodes.

Inhibitors,Modulators,Libraries The decrease in the gene for diacyl glycerol kinase and increase in CDP diglyceride synthase suggests an early switch Inhibitors,Modulators,Libraries in signaling pathways within glia. Table 4 summarizes the largest changes seen with each of the three cytokine mixtures, with the 12 most upregulated genes arranged in order from highest to lowest, and the 12 downregulated genes from most downregulated to least downregulated. While the magnitude of change in gene expression does not necessarily reflect the extent of bio logical relevance, the summary illustrates a number of changes in common between Th1 and MM cytokines, as predicted by their predominance of proinflammatory cytokines. Very few genes were upregulated by Th2 cytokines in the categories analyzed in this study, only the 12 genes shown in the table.

VascularIschemiaHypoxia It has been reported that certain MS lesions have features characteristic of ischemic or hypoxic injury to oli godendrocytes although inflammatory cells, par ticularly macrophages, are present in the lesions. Studies of normal appearing white matter in MS, employing gene array technology, selleck chem have also shown changes in patterns of gene regulation consistent with ischemia and the response to ischemia. It has also been suggested that local ang iogenesis occurs in EAE and in MS.