DNA microarray-based approach for identifying new therapeutic targets in neuroimmunological diseases

点击翻译按钮获取中文摘要

Using a custom cDNA microarray, we have analyzed gene expression profiling of peripheral blood T cells derived from multiple sclerosis (MS) who are untreated or treated with interferon (IFN)-β. This study was aimed at obtaining insights into the pathogenesis of MS and the mechanism of action of IFN-β. We have found that a number of genes up- or down-regulated in MS T cells, are those related to apoptosis, inflammation, or DNA damage-regulation. Among apoptosis-related genes up-regulated in MS, we have chosen Nurr4A2 (Nurrl) and analyzed the implication in depth. NR4A2 is known to target osteopontin (OPN), a Th1 cytokine, thought to be involved in the pathogenesis of MS. We hypothesized that NR4A2 and OPN might be coordinately altered in MS, but this was not the case. Rather, we found that expression of NR4A2 would strongly correlate with that of IkB alpha and IkB ipsilon, targeted by NFkB or that of TNFAIP3, that is inducible with TNF signaling. This suggests that NFkB linked signals would cause the change of gene expression, which is probably corrected by anti-inflamunatory therapy. We also investigated IFN-responsive genes in human MS by analyzing the blood from IFN-treated patients. Immediately induced genes contained inflammatory cytokines such as IL-6 and inflammatory chemokines such as CXCR3 ligand, which would account for the early side effects of IFN-b in MS patients, including headache and fever up. These results may suggest the importance of anti-inflammatory therapy in MS.