Glucocorticoids prime the inflammatory response of human hippocampal cells through up-regulation of inflammatory pathways.

Abstract

Increased pro-inflammatory cytokines and an overactive hypothalamic-pituitary-adrenal (HPA) axis have both been implicated in the pathogenesis of depression. However, these explanations appear contradictory because glucocorticoids are well recognised for their anti-inflammatory effects. Two hypotheses exist to resolve this paradox: the mediating presence of glucocorticoid receptor resistance, or the possibility that glucocorticoids can potentiate inflammatory processes in some circumstances. We sought to investigate these hypotheses in a cell model with significant relevance to depression: human hippocampal progenitor cells. We demonstrated that dexamethasone in vitro given for 24 hours and followed by a 24 hours rest interval before an immune challenge potentiates inflammatory effects in these neural cells, that is, increases the IL-6 protein secretion induced by stimulation with IL-1β (10 ng/mL for 24 hours) by + 49% (P < 0.05) at a concentration of 100 nM and by + 70% (P < 0.01) for 1 μM. These effects are time- and dose-dependent and require activation of the glucocorticoid receptor. Gene expression microarray assays using Human Gene 2.1st Array Strips demonstrated that glucocorticoid treatment up-regulated several innate immune genes, including chemokines and Nod-like receptor, NLRP6; using transcription factor binding motifs we found limited evidence that glucocorticoid resistance was induced in the cells. Our data suggests a mechanism by which stress may prime the immune system for increased inflammation and suggests that stress and inflammation may be synergistic in the pathogenesis of depression.

• Authors: Mark A Horowitz, Annamaria Cattaneo, Nadia Cattane, Nicola Lopizzo, Luis Tojo, Natalia Bakunina, Ksenia Musaelyan, Alessandra Borsini, Particia A Zunszain, Carmine M Pariante
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 87 Pg. 777-794 (07 2020) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 32194233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Glucocorticoids
• Receptors, Glucocorticoid
• Dexamethasone

Topics

• Dexamethasone (pharmacology)
• Glucocorticoids (pharmacology)
• Hippocampus (metabolism)
• Humans
• Pituitary-Adrenal System (metabolism)
• Receptors, Glucocorticoid (metabolism)
• Up-Regulation