INVOLVEMENT OF THE CYSTINE TRANSPORT-SYSTEM X(C)(-) MACROPHAGE-INDUCED GLUTAMATE-DEPENDENT CYTOTOXICITY TO NEURONS

Macrophages have been found to release glutamate and thereby induce ne uronal cell death by excitotoxicity, a mechanism that seems to be oper ative in various neurologic diseases. In this study, it is shown that the presence of both cystine and glutamine in the culture medium is in dispensable for brain macrophages to release glutamate and to cause ne uronal cell death.Furthermore, releaseof glutamate requires protein sy nthesis since cycloheximide prevented accumulation of the neurotoxic m olecule in supernatants of microglial cell cultures. Aminoadipate, whi ch was shown to inhibit the uptake of cystine by system x(c)(-) in fib roblasts, efficiently reduced the release of glutamate. The requiremen t of glutamine and cystine for the release of glutamate by microglial cells as well as the inhibitory effect observed with aminoadipate show s the transport system x(c)(-) to be essential for the release of the excitotoxin glutamate by microglial cells. Phagocytosis of zymosan par ticles and stimulation with different bacterial components, such as LP S, protein A, tuberculin, and Staphylococcus enterotoxin A increased g lutamate release two- to threefold above basal values. In addition, th e effect of bacterial components was mimicked by TNF-alpha, but not by IL-1 and IL-6. Cytokines known to deactivate macrophages, such as TGF -beta, IL-4, and IL-10, did not affect the transport system x(c)(-) in microglial cells. However, dexamethasone suppressed the glutamate rel ease up to 50%.