DNA fragmentation is reduced in anterior cingulate cortex of schizophrenics, but not bipolars

Abstract

Tumor necrosis factor-α (TNF-α) is a major mediator of inflammation and it is involved in many neurological disorders such as multiple sclerosis. Levels of TNF-α and lymphotoxin-α have been found elevated in plaques, bloods, and cerebral spinal fluids from multiple sclerosis patients. The expression of myelin basic protein (MBP), a major protein of the myelin sheath, is affected by cytokines secreted by activated immune cells. To determine the signal transduction pathway involving tumor necrosis factor’s action in myelination and demyelination, we have cloned and analyzed cis-elements on promoters of the human and mouse MBP genes. There are two putative nuclear factors kappa-B (NF-κB) cis-elements on the human and one on the mouse gene promoter. In an electrophoretic mobility shift assay, all three NF-κB cis-elements showed binding to a protein, which was recognized by an antibody against NF-κB P65 component. The specificity of the binding was demonstrated in a competitive assay using NF-κB consensus oligonucleotides. A two base pair site-directed mutation on the mouse NF-κB cis-element abolished its binding activity. We created a DNA construct by linking the mouse MBP gene promoter containing the NF-κB cis-element to luciferase gene. Transfection of this construct into a human oligodendroglioma cell line showed TNF-α increased the transgene expression. Furthermore the mutation of NF-κB site abolished TNF-α -induction of the transgene. The data demonstrate that NF-κB is the mediator between tumor necrosis factor’s action and MBP gene expression. Elucidating the molecular mechanisms underlying TNF-α regulation of MBP gene expression provides new scientific bases for the development of therapy against oligodendrocyte-specific and myelin-related disorders such as multiple sclerosis.