Context-dependent IL-6 potentiation of interferon- gamma-induced IL-12 secretion and CD40 expression in murine microglia.
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 (IFNgamma)-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, IFNgamma-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 IFNgamma 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, IFNgamma or GMCSF will alter the type and amplitude of their response.
Lin
Hsiao-Wen
HW
Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan.
Levison
Steven W
SW
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D019013:CD40 Antigens; D020934:Ciliary Neurotrophic Factor; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D018664:Interleukin-12; D014443:Tyrosine; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor