Interleukin-6 (IL-6), a 26 kDa, alpha-helical protein, is produced locally in the nervous system by astrocytes, microglia, and neurons, and is important in activating infiltrating macrophages, regulating B cell growth and differentiation as well as inducing T cell responses (Frei

Interleukin‐6 (IL‐6) is produced by neurons, astrocytes, and microglia, and elevated levels of IL‐6 within the CNS have been documented in multiple neurological disorders including Alzheimer’s disease, stroke, epilepsy, attention deficit disorder, cerebral palsy, and multiple sclerosis. Here, we sought to understand how IL‐6 regulates microglial signal transduction and their immune properties. Using highly enriched cultures of neonatal murine microglia we show that IL‐6 alone has direct effects on microglia as it activates STAT3 and extracellular signal‐regulated kinase pathways in a time‐ and dose‐dependent fashion and it enhances interferon‐gamma (IFNγ)‐stimulated IL‐12 secretion. However, other immune properties were only weakly modulated by IL‐6 when administered without the soluble IL‐6 receptor (sIL‐6R). For instance, IFNγ‐induced expression of the co‐stimulatory molecule, CD40 was dependent on sIL‐6R administration. IL‐6 with or without sIL‐6R did not affect major histocompatability complex class II expression. In granulocyte–macrophage colony‐stimulating factor (GMCSF)‐induced dendritic cell‐like microglia, IL‐6/sIL‐6R and IFNγ stimulated an even greater increase in CD40 expression compared with primary microglia. Altogether, our results demonstrate that microglial responses to IL‐6 are not simple in that the effects of IL‐6 are context‐dependent. In particular, the presence or absence of sIL‐6R, IFNγ or GMCSF will alter the type and amplitude of their response.