Tumor necrosis factor alpha (TNF) induced alterations in brain microvessel endothelial cell (BMEC) permeability

The blood-brain barrier (BBB) plays an important role in the regulation of solutes in the CNS. BBB disruptions have been positively correlated with the severity of clinical symptoms in several cerebral inflammatory diseases including multiple sclerosis, meningitis, AIDS-related dementia, and ischemia. Identification of the endogenous factors involved in BBB disruption and understanding their mechanisms of action could improve clinical outcome from these diseases.; TNF is increased in the brain and CSF during inflammatory diseases of the CNS. While TNF has been reported to increase cerebral microvascular permeability, the complete cellular signaling pathway responsible for alterations in cerebrovasculature permeability following TNF is unclear. Previous studies suggested cyclooxygenase (COX) induced cytoskeletal alterations were responsible for the increased cerebrovascular permeability following TNF. However, the upstream signaling events that trigger COX induction and the resulting permeability changes in BMEC remain to be determined.; This research used primary cultured BMEC to identify upstream components involved in TNF-induced BBB permeability alterations. Nuclear factor kappa B (NF-kB) and nitric oxide (NO) were examined as potential upstream mediators of the TNF response in the cerebral microvasculature. In both in vitro and in vivo, NF-kB inhibitors inhibited prostaglandin release and permeability changes following TNF. Separate studies found no significant changes in nitric oxide synthase expression or NO release following TNF. NO pathway inhibition suppressed the TNF induced increased permeability, but had no effect on COX-2 induction or prostaglandin release. This suggests that NO and NF-kB/COX-2 pathways are acting in parallel with at least small amounts of NO essential for the TNF response.; The potential role of TNF in BBB alterations following inflammatory stimuli, like lipopolysaccharide (LPS) or hypoxia, were examined. Following LPS or hypoxia, there was a significant increase in TNF and prostaglandins release from BMEC that was correlated with increased BMEC permeability. Thus, these studies suggest that BBB disruption observed during inflammatory stimuli are at least partly due to activation of TNF mediated signaling pathways.