Molecular and cellular effects of glucocorticoids, inflammation and antidepressant compounds in a cellular model of depression

Student thesis: Doctoral ThesisDoctor of Philosophy


Chronic psychological stress has been thought to induce depression through increased activity of both the innate immune system and the hypothalamic-pituitary-adrenal (HPA) axis. The co-existence of high levels of pro-inflammatory cytokines and cortisol, produced by these systems, respectively, has presented a conundrum, given the potent anti-inflammatory properties of cortisol. Recently noted pro-inflammatory effects of glucocorticoids, or the presence of glucocorticoid resistance have been proposed to explain this relationship. In turn, antidepressant compounds (monoaminergic and polyunsaturated fatty acids (PUFAs)) may work by counteracting inflammation and its effects on the brain – including altering levels of inflammation, and reversing the effects of inflammation on hippocampal neurogenesis and the kynurenine metabolic pathway. I have used human hippocampal progenitor cells (HPC03A/07) to investigate these processes in a cell model with relevance to depression.

While glucocorticoids were anti-inflammatory upon co-incubation with inflammatory stimulation in these cells, they were pro-inflammatory when their treatment preceded inflammatory stimulation. Pre-treatment with dexamethasone potentiated subsequent inflammatory response by 72.2% and pre-treatment with cortisol potentiated responses by 49.3%, as measured by IL-6 secreted into the supernatant following IL-1β stimulation. These effects were dose-dependent, such that intermediate doses produced the greatest effects, while higher and lower doses produced smaller effects; they were also time-dependent, with an interval between glucocorticoid treatment and inflammatory stimulation of 24 hours producing a significant potentiation effect, with 1 hour, 12 hours and 48 hours producing no effect. Inflammatory potentiation was also dependent on the glucocorticoid receptor (GR) as it could be abrogated by treatment with the GR antagonist, RU486. These potentiation effects were observed for a variety of cytokines and chemokines secreted in response to IL-1β treatment - IL-8, IP-10, IL-1RA, RANTES, and MCP-1. There was some evidence that the underlying mechanism involved the induction of glucocorticoid resistance as there was a reduction in the ability of glucocorticoids to inhibit inflammation upon re-exposure, and GR-target genes were down-regulated following dexamethasone pre-treatment. There was also evidence that glucocorticoid treatment up-regulated immune pathways, including the important stress sensing protein from the NOD-like receptor family, pyrin domain containing 6 gene (NLRP6).

A systematic literature review of clinical studies that measured glucocorticoid levels, pro-inflammatory cytokines and glucocorticoid resistance found a strong association between the presence of glucocorticoid resistance and increased levels of pro-inflammatory cytokines, quantified by meta-analysis (Fisher’s z = 0.38), though not between cortisol levels and pro-inflammatory cytokines.

The effects of the monoaminergic antidepressants (venlafaxine and sertraline) and the PUFAs (EPA and DHA) on stimulated levels of inflammation, IL-1β-induced reductions in neurogenesis, and associated increases in the neurotoxic kynurenine metabolite, quinolinic acid (QUIN) were investigated. The antidepressant compounds diverged in their effect on immune processes, with venlafaxine and EPA reducing the amount of cytokines and chemokines secreted in response to IL-1β stimulation, while DHA and sertraline potentiated this response. Interestingly, all compounds reduced the activity of NF-κB. Sertaline, venlafaxine and DHA all reversed IL-1β-induced reductions in hippocampal neurogenesis, and increases in QUIN; conversely, EPA did not affect levels of neurogenesis or levels of QUIN.

Overall, these results indicate that glucocorticoids can exert pro-inflammatory effects in human hippocampal cells, by a mechanism involving upregulated immune pathways and glucocorticoid resistance, potentially explaining the co-existence of HPA axis and innate immune dysfunction in depression. Antidepressant compounds act through different mechanisms in human hippocampal cells, with EPA largely affecting immune processes directly, while DHA, venlafaxine and sertraline affected inflammation-induced changes to neurogenesis, potentially through their effect on the kynurenine metabolic pathway.
Date of Award2016
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPatricia Zunszain (Supervisor) & Carmine Pariante (Supervisor)

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