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A Simple and Efficient Method for Testing Immunomodulatory Agents for Generation of Tolerogenic Dendritic Cells from Human CD14+ Monocytes
Published on: April 11, 2025
359
The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential
Mohammed Ghiboub1,2, Matthew Bell2, Dovile Sinkeviciute2
1Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands.
Current Issues in Molecular Biology
|May 26, 2023
Summary
Inhibiting the SP140 protein with GSK761 reduces inflammatory responses in dendritic cells (DCs). This suggests targeting SP140 may help treat autoimmune and inflammatory diseases by promoting immune tolerance.
Area of Science:
- Immunology
- Molecular Biology
- Epigenetics
Background:
- SP140 is an epigenetic reader protein implicated in immune cells.
- Genetic variations in SP140 are linked to autoimmune and inflammatory diseases.
- SP140 inhibition in macrophages reduces inflammatory cytokine expression.
Purpose of the Study:
- To investigate the effects of the SP140 inhibitor GSK761 on human dendritic cell (DC) differentiation and maturation.
- To assess the impact of SP140 inhibition on cytokine production and T-cell stimulation by DCs.
- To explore the potential of targeting SP140 for treating immune-mediated diseases.
Main Methods:
- Human DCs were treated with GSK761 or SP140 siRNA.
- Lipopolysaccharide (LPS) was used to stimulate DCs.
- Expression of cytokines, co-stimulatory molecules, and maturation markers was analyzed.
- T-cell activation and phenotypic changes were assessed following DC stimulation.
Main Results:
- LPS increased SP140 expression and recruitment to pro-inflammatory cytokine gene promoters in DCs.
- GSK761 treatment reduced LPS-induced TNF, IL-6, and IL-1β expression in DCs.
- GSK761 inhibited DC maturation, reducing CD83, CD80, CD86, and CD1b expression.
- T cells stimulated by GSK761-treated DCs showed reduced TBX21/RORA and increased FOXP3 expression, indicating regulatory T cell generation.
Conclusions:
- SP140 inhibition impairs DC maturation and pro-inflammatory cytokine production.
- Targeting SP140 promotes tolerogenic properties in DCs.
- SP140 inhibition offers a potential therapeutic strategy for autoimmune and inflammatory diseases.
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