Pro- and Anti-Inflammatory Properties of Interleukin in Vitro: Relevance for Major Depression and Human Hippocampal Neurogenesis

Abstract

Background Although the pro-inflammatory cytokine, interleukin (IL)6, has been generally regarded as “depressogenic”, recent research has started to question this assumption, in light of the fact that this cytokine can also have anti-inflammatory properties. This bimodal action seems to be dependent on its concentration levels, and on the concomitant presence of other pro-inflammatory cytokines. Methods We exposed a human hippocampal progenitor cell line HPC0A07/03C to cytokine levels described in depressed patients (IL6 5pg/ml with IL1β 10pg/ml or Macrophage Migration Inhibitory Factor (MIF) 300pg/ml), in healthy subjects (IL6 with IL1β, 1pg/ml or MIF 10pg/ml), as well as to the potentially anti-inflammatory, much higher concentrations of IL6 (50000pg/ml). Results Treatment with high concentrations of IL6 with IL1β or MIF (resembling depressed patients) decreases neurogenesis when compared with low concentrations of the same cytokines (healthy subjects), and that this is mediated via production of, respectively, IL8 and IL1β in cell supernatant. Instead, treatment with the very high, anti-inflammatory concentration of IL6 (50000pg/ml) together with high IL1β or MIF prevents the decrease in neurogenesis and reduces both IL8 and IL1β. When the high concentrations of both IL1β and MIF were used in co-treatment, as a model of treatment resistant depression, we also demonstrate a reduction in neurogenesis, and that this is mediated via a decrease in IL4; moreover, co-treatment with high IL1β and MIF and the very high concentration of IL6 prevents the reduction in neurogenesis, and increases IL4. Conclusions Our results demonstrate that IL6 can exert both pro- and anti-inflammatory (potentially antidepressant) properties, depending on its concentrations and combinations with other inflammatory cytokines.

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis

“…Fixed cells were stained for markers of immature and mature neurons using respectively doublecortin (DCX; Alexa 488 donkey anti-rabbit; 1:1000, Invitrogen) and microtubule-associated protein 2 (Map2; Alexa 555 donkey anti-mouse, 1:1000, Invitrogen), whereas apoptotic cells were examined using caspase 3 (CC3; Alexa 555 donkey anti-rabbit, 1:1000, Invitrogen). All cells were labelled using DAPI dye, as in previous publications [13,20,21] (see also Supplementary Materials). The number of DCX and Map2 positive cells over total DAPI positive cells was counted using an insight automated imaging platform (CellInsight) (Supplementary Fig.…”

“…Cell supernatants were used for cytokines measurement (IL1β, IL6 or IFN-α), using the Human ProInflammatory Singleplex Very-Sensitive Kit from Meso Scale Discovery (MSD) (Gaithersburg, MD) and the SECTOR Imager MSD device, according to the manufacturers' instructions. Detailed information on the cytokines analyses procedure can be found in our previous publication [21].…”

“…In particular, cytokines have been shown to alter neurogenesis, a mechanism potentially disrupted in depression, and required for antidepressant efficacy [17][18][19]. Indeed, using the aforementioned human hippocampal progenitor cells, we have previously demonstrated the ability of IL1β, IL6 and interferon-alpha (IFN-α) to cause reduction in cell proliferation and neurogenesis, and increased apoptosis, via activation of the downstream inflammatory signalling pathways, transcription factor signal transducer and activator of transcription 1 (STAT1) and nuclear factor-kappa B (NF-kB) [13,20,21].…”

“…Considering the limited evidence for the role of these metabolites in the mechanism underpinning the antiinflammatory and neurogenic activities of ω-3 PUFAs in the context of depression, we used our aforementioned, validated in vitro model of 'depression in a dish' [13,20,21,[29][30][31][32][33] exposing immortalised human hippocampal progenitor cell line HPC0A07/03C to candidate 'depressogenic' cytokines, IL1β, IL6 and IFN-α, resulting in a reduction in neurogenesis and an increase in neuronal apoptosis [13,20,21]. In order to identify the lipid species or families of COX-, LOX-or CYP450-derived mediators putatively involved in the anti-inflammatory and neuroprotective effects exerted by ω-3 PUFAs, we pre-treated cells with EPA/DHA with or without a selective inhibitor of COX-, LOX-or CYP450 enzymes, and then directly exposed cells to candidate metabolites.…”

What can neuroimmunology teach us about the symptoms of long-COVID?

“…Interestingly, cognitive dysfunction appears to be one of the main symptoms linked to increased levels of inflammatory markers [ 10 , 48 ]. The molecular pathways through which central inflammation contributes to depression and cognitive dysfunction are still partly unclear, but preclinical evidence suggests that central neuroinflammation may contribute to reduced neurogenesis particularly in the hippocampus, one of the main structures involved in cognitive function and memory [ 26 , 48 ]. Other potential pathways include effects of synthesis of serotonin following the activation of kynurenine pathways [ 49 , 50 ] and an unbalance in oxidative stress markers [ 39 ].…”