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Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system and is generally considered to be autoimmune in nature. We previously demonstrated that the transcription factor Sp3 is significantly down-regulated in immune cells from MS patients. The potential role of Sp3 down-regulation in MS pathogenesis is not well understood. Sp3's function was assessed in vitro after siRNA-mediated knockdown of its transcript in Jurkat cells. Sp3 protein levels were knocked down an average of 70%. ELISA studies demonstrated decreased production of IL-10 and TGF beta 1 and increased production of TNF alpha (p<0.05 in all assays). Subsequent microarray analysis demonstrated significantly altered expression of 37 genes (p<0.001 for each gene) compared with Glyseraldehyde-3-phosphate dehydrogenase (GAPDH) knockdown samples and with untreated controls. Analysis showed differential expression (p<0.005) of 13 gene pathways. Many of the genes and pathways that have been regulated by the knockdown of Sp3 are involved in immune function, specifically in the areas of apoptosis, cell-to-cell adhesion, integrin signaling, T-cell differentiation, and stimulation of proinflammatory cytokines. This study demonstrates the mechanisms by which Sp3 may regulate immune function and suggest a basis for its potential contribution to MS disease pathogenesis.
