The innate immune system plays a crucial role in protecting the host against infectious microorganisms. An inappropriate control of this system may have profound consequences, because of the maintained production of specific proinflammatory molecules. Glucocorticoids are the most efficient endogenous molecules that provide negative feedback on proinflammatory signaling and gene expression. Here we show that activation of this system is not detrimental for the brain but a profound neurodegeneration takes place in animals treated with the glucocorticoid receptor inhibitor Mifepristone (RU486). This drug increased the inflammatory reaction induced by a single intracerebral bolus of lipopolysaccharide (LPS). Inhibition of tumor necrosis factor alpha (TNF-alpha) totally abolished the neurotoxic effect of the endotoxin, and chronic infusion of the cytokine mimicked the treatment combining RU486 and LPS. The neuronal damage caused by TNF-alpha is dependent on both nitric oxide and caspase pathways. In controlling the cerebral innate immunity and microglial TNF-alpha production, glucocorticoids play a major role in protecting the brain against bacterial cell wall components.