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.