期刊
BMC NEUROSCIENCE
卷 19, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12868-018-0460-x
关键词
Minocycline; Retinoic acid; Neuroinflammation; Microglia; Cytokines
资金
- Charite Universitatsmedizin Berlin
- Berlin Institute of Health
- Deutsche Forschungsgemeinschaft [he 6939]
- Bundesministerium fur Bildung und Forschung [01EE1401F]
Background: Minocycline is a lipophilic tetracycline of increasing appeal in neuroscience as it inhibits microglial activation, a mechanism involved in numerous neuropsychiatric disorders. Own data point towards retinoid-mediated effects of minocycline in murine brain and skin, and towards a vicious cycle of neuroinflammation which is driven by microglial activation-induced breakdown of local retinoids such as retinoic acid (RA). We therefore sought to study minocycline's anti-inflammatory effects on human microglial-like monocyte-derived cells in the context of retinoid signaling. Results: As hypothesized, minocycline exposure resulted in a substantial increase of RA levels in the human monocytic cell line THP-1. While pro-inflammatory stimulation with lipopolysaccharides resulted in increased tryptophanedegrading indoleamine-2,3-dioxygenase IDO-expression and TNF-alpha levels in primary human monocyte-derived microglial-like cells, this effect was attenuated by minocycline only in the presence of retinoids. The anti-inflammatory effects of minocycline on TNF-alpha expression were completely abolished by a pharmacological blockage of retinoic acid receptors (RARs) using BMS-493 and unaffected by selectively blocking retinoid-X-receptors using UVI-3003. Conclusions: Our data indicate for the first time a RA-dependent, anti-inflammatory effect for minocycline in human microglial-like cells via inhibition of local RA turnover. The RA-dependent mode of action for minocycline appears to be predominantly mediated through RAR-signaling.
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