SYNERGISTIC NEUROTOXIC EFFECTS OF COMBINED TREATMENTS WITH CYTOKINES IN MURINE PRIMARY MIXED NEURON GLIA CULTURES/

Activation of brain glial cells with the bacterial endotoxin lipopolys accharide (LPS), the HIV-1 coat protein gp120, or beta-amyloid-derived peptides, stimulates the expression of several cytokines, including t umor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1) and IL-6, and nitric oxide (NO) which have been proposed as causes of neurodege neration in the brain. In the present study, the neurotoxic effects of several cytokines, alone or in various combinations, and the correlat ions of the release of lactate dehydrogenase, the loss of neurons, and the secretion of NO in brain neuronal cell injury were investigated i n murine primary mixed neuronal/glial cell cultures. A specific combin ation of cytokines, i.e., IL-1 (1 ng/ml) + TNF alpha (10 ng/ml)/interf eron-gamma (IFN gamma) (200 u/ml), induced a dramatic neuronal cell in jury in the neuron/glia cultures, and its cytotoxic profile was very s imilar to that seen with the LPS/IFN gamma-induced neuron injury. This indicates that among the many toxic immune mediators secreted in resp onse to LPS, IL-1 and TNF alpha can mimic LPS as the triggering signal s and primary mediators for glia-mediated neuron injury in the presenc e of IFN gamma. This study provides new insights about the cytotoxic m echanism(s) for cytokine-mediated neuron injury. (C) 1998 Published by Elsevier Science B.V.