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The Journal of Neuroscience, July 2, 2003, 23(13):5536-5544
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Glucocorticoids Play a Fundamental Role in Protecting the Brain during Innate Immune Response
Sylvain Nadeau and
Serge Rivest
Laboratory of Molecular Endocrinology, Centre Hospitalier de
l'Université Laval Research Center and Department of Anatomy and
Physiology, Laval University, Québec, Canada G1V 4G2
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 
(TNF-) 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- is dependent on both nitric
oxide and caspase pathways. In controlling the cerebral innate immunity and
microglial TNF- production, glucocorticoids play a major role in
protecting the brain against bacterial cell wall components.
Key words: caspases; cytokines; gram-negative cell wall component; inflammation; innate immunity; microglia; neurodegeneration; NF- B; TNF-
Received Feb. 4, 2003;
revised Apr. 9, 2003;
accepted Apr. 21, 2003.
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