Chronic Unpredictable Stress Exacerbates Lipopolysaccharide-Induced Activation of Nuclear Factor-κB in the Frontal Cortex and Hippocampus via Glucocorticoid Secretion

Abstract

Although the anti-inflammatory actions of glucocorticoids (GCs) are well established in the periphery, these stress hormones can increase inflammation under some circumstances in the brain. The transcription factor nuclear factor-B (NF-B), which is inhibited by GCs, regulates numerous genes central to inflammation. In this study, the effects of stress, GCs, and NMDA receptors on lipopolysaccharide (

An inflammatory review of glucocorticoid actions in the CNS

“…The studies that have looked at the effects of chronic GC exposure have also found similar results for basal GCs: locking GCs at basal levels augments excitotoxin-induced upregulation of IL-1β and TNF-α expression and protein levels in the hippocampus (Dinkel et al 2003). Pharmacological inhibition of GR increases TNF-α, IL-1 beta, and iNOS protein levels in rats given LPS peripherally (Munhoz et al 2006). Moreover, in hippocampal cultures, low concentrations of corticosterone inhibit excitotoxin-induced expression of IL-1β and TNF-α (MacPherson et al 2005).…”

“…Commensurate with that, in unstressed rats, GR antagonists increase LPS-induced NFκB DNA binding activity in the frontal cortex and hippocampus (Munhoz et al 2006). Moreover, dexamethasone treatment decreases basal NFκB DNA binding activity in cortex and hippocampus (Unlap and Jope 1995;Unlap and Jope 1997) and also following LPS treatment (Wang et al 2006) (however there are some caveats to this interpretation that will be discussed later.…”

“…CUS fails to suppress the increased expression of IL-1β and TNF-α following infusion of LPS into the prefrontal cortex (de Pablos et al 2006). Even more striking, CUS augments TNF-α, IL-1β , and iNOS protein levels in hippocampus and cortex when LPS is administered peripherally, an effect that is GR-mediated (Munhoz et al 2006). Similarly, high stress concentrations of corticosterone exacerbate excitotoxin-induced increases in IL-1β and TNF-α mRNA and protein levels both in vivo and in vitro (Dinkel et al 2003;MacPherson et al 2005).…”

“…In contrast, CUS increases LPS-induced NFκB DNA binding and protein levels in these brain structures (Figure 3), a GR-mediated effect (Munhoz et al 2006). Moreover, CUS following direct LPS infusion into the prefrontal cortex increases components of the MAPK signaling pathway involved in inflammatory pathogenesis including phosphorylated JNK, p38, and ERK (de Pablos et al 2006).…”

“…Finally, and perhaps most compellingly, GC-enhanced neuroinflammation can occur in the absence of neuron death (i.e. from peripheral LPS administration) (Munhoz et al 2006;Munhoz in prep).…”