Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 87, Issue -, Pages 777-794Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2020.03.012
Keywords
Inflammation; Glucocorticoids; Depression; Cytokines; Chemokines; Pro-inflammatory; Glucocorticoid resistance; NOD-like receptor; NLRP6; Hippocampal progenitor cells; Dexamethasone
Categories
Funding
- NARSAD Young Investigator Award
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
- Commission of European Communities 7th Framework Programme Collaborative Project [n22963]
- King's Overseas Research Studentship (King's College London)
- King's College London
- MRC [MR/N029488/1] Funding Source: UKRI
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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-1 beta (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 mu M. 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.
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