This enzyme is markedly upregulated during differentiation of oligodendroglia and synthesizes galactocerebroside, the major glycolipid of myelin and precursor to sulfatide. An early response to inflammatory cytokines has not been pre viously reported for the therefore gene or the protein. Notably Th1 cytokines upregulated the gene for phos pholipid scramblase, which translocates phospholipids from one surface of the plasma membrane to the other. In our initial paper we reported that Th1 and MM cytokines induced robust upregulation of genes for ABC transporter 1, which among its several functions, translo cates phosphatidyl choline and cholesterol to the outer membrane leaflet in astrocytes and neurons, and for ABC transporter 2, active in oligodendrocytes during mye lination.

The ABC transporters Inhibitors,Modulators,Libraries are also important in intraceullar transport of other proteins including peptide epitopes with MHC class I molecules. Lipid signaling Th1 cytokines Inhibitors,Modulators,Libraries downregulated the gene for diacyl glycerol kinase beta, which phosphorylates diacyglycerol to pro duce phosphatidic acid, leading to termination of diacylg lyceryol signaling via PKC, Ras GTPase and other signaling pathways. IL 2, one of the components of the Th1 mixture, upregu lates diacylglycerol kinase in myelin, raising the possibility that oligodendroglia are upregulating this gene in response to the Th1 cytokines. In addition, the gene for CDP diacylglycerol synthase, the enzyme that synthesizes phosphatidyl inositol from phosphatidic acid, is robustly upregulated by both Th1 and MM cytokines, suggesting a switch from diacylglycerol to phosphatidyl inositol medi ated signaling pathways.

Conversely, the gene for myo inositol monophosphatase was downregulated by MM cytokines. Inhibitors,Modulators,Libraries this enzyme, the key enzyme inhibited by lith ium, generates free inositol from inositol 3 phosphate derived from glucose 6 phosphate, and regulates levels of inositol available for synthesis of phosphatidyl inositol and its multi phosphorylated derivatives critical for intra cellular signaling and trafficking as well as calcium home ostasis. It is of note that lithium is currently being evaluated as a treatment of amyotrophic lateral sclerosis based on its effects on inositol pathways. Sphingosine 1 phosphate plays a key role in cell survival and inflammatory responses. the gene for one of its receptors, Inhibitors,Modulators,Libraries EDG was down regulated by both MM and Th2 cytokines.

There has been a phase II trial in patients with MS of an oral agent called FTY72, which binds to the EDG recep tor. A large Phase III study Inhibitors,Modulators,Libraries is under way. Inhibition of this receptor both blocks emigration from and favors homing of lymphocytes INCB018424 to secondary lymph structures, ostensibly without affecting T cell via bility or inhibiting memory T cells. In experimental ani mals other inflammatory cells, such as monocytes and mature dendritic cells, are also affected and the protein is also found on endothelial cells.