MAST-CELL ACTIVATION CAUSES DELAYED NEURODEGENERATION IN MIXED HIPPOCAMPAL CULTURES VIA THE NITRIC-OXIDE PATHWAY

Mast cells are pleiotropic bone marrow-derived cells found in mucosal and connective tissues and in close apposition to neurons, where they play important roles in tissue inflammation and in neuroimmune interac tions. Connective tissue mast cells, with which intracranial mast cell s share many characteristics, contain cytokines that can cause inflamm ation. Here, we report that myelin basic protein, a major suspected im munogen in multiple sclerosis, as well as an antigenic stimulus, provo kes mast cells to trigger a delayed cytotoxicity for neurons in mixed neuron-glia cultures from hippocampus. Neurotoxicity required a prolon ged period (12 h) of mast cell incubation, and appeared to depend larg ely on elaboration of the free radical nitric oxide by astrocytes. Act ivation of astrocytes was mediated, in part, by mast cell-secreted tum or necrosis factor-alpha. Myelin basic protein and 17 beta-estradiol h ad a synergistic action on the induction of mast cell-associated neuro nal injury. The cognate mast cell line RBL-2H3, when subjected to an a ntigenic stimulus, released tumor necrosis factor-alpha which, togethe r with exogenous interleukin-1 beta (or interferon-gamma), induced ast roglia to produce neurotoxic quantities of nitric oxide. A small but s ignificant proportion of mast cell-derived neurotoxicity under the abo ve conditions occurred independently of glial nitric oxide synthase in duction. Further, palmitoylethanolamide, which has been reported to re duce mast cell activation by a local autacoid mechanism, decreased neu ron loss resulting from mast cell stimulation in the mixed cultures bu t not that caused by direct cytokine induction of astrocytic nitric ox ide synthase. These results support the notion that brain mast cells c ould participate in the pathophysiology of chronic neurodegenerative a nd inflammatory diseases of the nervous system, and suggest that down- modulation of mast cell activation in such conditions could be of ther apeutic benefit.