Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein-protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain.

The proper functioning of the neuron-microglia-astrocyte triad is fundamental for the maintenance of central nervous system (CNS), since neurodegenerative and aging processes may be related to a "defective" cellular interaction between neurons and glia. Activation and recruitment of glial cells are complex processes and require well-organized intercommunication between neurons and glial cells as well as between glial cells. Despite the well-established anti-inflammatory effect of glucocorticoids (GCs), it has been shown that, in the CNS, increased levels of this hormone may potentiate some aspects of the inflammatory response, for example the activation of the lipopolysaccharide-induced NFKB transcription factor and the evidence pointing to the cellular specificity of these actions is increasing. This study aims to characterize the effects of GCs on physical and humoral cellular interactions between astrocytes, microglia, and neurons in the presence of an acute inflammatory stimulus, LPS, in in vitro primary cell cultures derived from the brain cortex of neonatal rats. We verified that GCs are not anti-inflammatory since they do not decrease the activation of NFKB and yet potentiate the LPS-induced cell death in mixed cultures. Astrocytes in mixed, neuron-and astrocyte-enriched cultures have different responses to LPS, as well as previous treatment with GCs, regarding the nuclear localization of RELA, an indication of its activation. Our results in this cell type suggest that GCs are proinflammatory and this action seems to depend on cell interactions and the presence of GR / MR heterodimers. Microglia participates in the response of astrocytes to LPS in relation to the nuclear localization of RELA.

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