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Effect of thalidomide on chemokine production by human microglia
J R Lokensgard1, S Hu, E M van Fenema
1Minneapolis Medical Research Foundation, Minneapolis, MN 55404, USA. loken006@tc.umn.edu
Insights
Thalidomide effectively inhibits interleukin-8 (IL-8) production in human microglial cells. This finding suggests thalidomide
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Thalidomide exhibits immunomodulatory effects, inhibiting cytokine production.
- Microglia play a key role in neuroinflammation, particularly in conditions like meningitis.
Purpose of the Study:
- To investigate thalidomide's impact on chemokine production in human microglial cells.
- To explore thalidomide's potential therapeutic role in bacterial meningitis.
Main Methods:
- Human microglial cells were stimulated with lipopolysaccharide.
- Chemokine production (RANTES, MCP-1, MIP-1beta, IL-8) was measured using ELISA.
- Intracellular IL-8 staining, IL-8 mRNA transcription, and NF-kappaB activation were analyzed.
Main Results:
- Thalidomide selectively and potently inhibited interleukin-8 (IL-8) production in a dose-dependent manner.
- Inhibition of IL-8 was linked to reduced intracellular IL-8 and mRNA levels.
- Thalidomide suppressed NF-kappaB activation in lipopolysaccharide-stimulated microglia.
Conclusions:
- Thalidomide demonstrates significant inhibition of IL-8 production by microglial cells.
- This mechanism suggests a potential therapeutic application for thalidomide in acute bacterial meningitis by reducing neutrophil chemotaxis.
Abstract:
Thalidomide, a psychoactive drug that readily crosses the blood-brain barrier, has been shown to possess immunomodulatory attributes, including the inhibition of cytokine production by monocytes and microglia. In this study, we investigated the effect of thalidomide on chemokine production by human microglial cells. Microglial cells were stimulated with lipopolysaccharide, a key cell-wall component of gram-negative bacteria responsible for meningitis, and production of chemokines (regulated upon activation normally T cell expressed and secreted [RANTES], monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1beta, and interleukin [IL]-8) was examined by ELISA. Thalidomide treatment was found to cause potent and selective inhibition of IL-8 production in a dose-responsive manner. This inhibition was associated with decreased intracellular IL-8 staining as well as reduced transcription of IL-8 mRNA. In addition, thalidomide treatment of lipopolysaccharide-stimulated microglia inhibited the activation of protein NF-kappaB, a transcription factor known to be important for IL-8 production. These results suggest thalidomide could have a therapeutic role in acute bacterial meningitis through inhibition of IL-8-mediated neutrophil chemotaxis.