By their property to release glutamate and reactive oxygen intermediates, macrophages may play an important role in neurotoxicity. In the present study we have investigated whether macrophage-derived molecules also impair the detoxification of glutamate by astrocytes. Cytokines, including interleukin (IL)-1, 6 and 10, interferon (IFN)-alpha/beta, tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta 1, as well as leukotriene (LT) B4 and C4, prostaglandin (PG) E2 and nitric oxide radicals had no effect on the uptake of [3H]glutamate by murine astrocytes in culture. In contrast, exposure of astrocytes to the enzyme glucose oxidase (100-200 mU ml-1), which maintains steady-state levels of hydrogen peroxide, reduced glutamate uptake by 30-50%. By their dual effect, comprising secretion of glutamate and inhibition of its detoxification by astrocytes, activated macrophages and microglial cells may contribute to exacerbate excitotoxic mechanisms in neurological diseases.