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Published on: January 7, 2019
SET8 participates in lipopolysaccharide-mediated BV2 cell inflammation via modulation of TICAM-2 expression
Yanjun Zhao1, Xijun Yang2, Fufen Meng3
1Department of Anesthesiology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.
Abstract:
Microglial inflammation, involved in the occurrence and development of sepsis-associated encephalopathy, exhibits upregulation of proinflammatory cytokine and proinflammatory enzyme expression, leading to inflammation-induced neuronal cell apoptosis. TIR domain containing adaptor molecule-2 (TICAM-2) participates in lipopolysaccharide (LPS) mediated BV2 cell inflammation. SET8 plays a crucial role in a variety of cellular signal pathways. In this study, we hypothesize that SET8 participates in LPS-mediated microglial inflammation via modulation of TICAM-2 expression. Our data indicated that LPS induced BV2 inflammation via upregulation of TICAM-2 expression. Moreover, LPS treatment inhibited SET8 expression, while it increased activating transcription factor 2 (ATF2) expression. The effects of sh-SET8 and ATF2 overexpression were similar to that of LPS treatments. Inhibition of TICAM-2 expression counteracted sh-SET8-mediated and ATF2 overexpression mediated BV2 cell inflammation. Further, SET8 was found to interact with ATF2. A mechanistic study found that H4K20me1, a downstream target of SET8, and ATF2 enriched at the TICAM-2 promoter region. Luciferase reporter assays indicated that sh-SET8 increased TICAM-2 promoter activity but augmented the effect of ATF2 overexpression on TICAM-2 promoter activity as well. Co-transfection of sh-SET8 with ATF2 overexpression more dramatically increased TICAM-2 expression in BV2 cells. The present study indicated that SET8 interacted with ATF2 to modulate TICAM-2 expression, which participated in LPS-mediated BV2 cell inflammation.
Insights
SET8 modulates microglial inflammation by interacting with ATF2 to regulate TICAM-2 expression, a key factor in lipopolysaccharide-induced inflammation and sepsis-associated encephalopathy.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglial inflammation drives sepsis-associated encephalopathy, causing neuronal apoptosis.
- TIR domain containing adaptor molecule-2 (TICAM-2) is implicated in lipopolysaccharide (LPS)-induced microglial inflammation.
- SET8 is a key regulator in cellular signaling pathways.
Purpose of the Study:
- To investigate the role of SET8 in LPS-mediated microglial inflammation.
- To determine if SET8 modulates TICAM-2 expression in this process.
- To elucidate the molecular mechanisms underlying SET8's function.
Main Methods:
- Utilized BV2 cell models treated with LPS.
- Assessed expression levels of SET8, TICAM-2, and ATF2.
- Performed co-immunoprecipitation and chromatin immunoprecipitation assays.
- Conducted luciferase reporter assays to analyze promoter activity.
Main Results:
- LPS upregulated TICAM-2 expression while downregulating SET8 and upregulating ATF2.
- SET8 inhibition or ATF2 overexpression mimicked LPS effects on inflammation.
- TICAM-2 inhibition ameliorated inflammation induced by SET8 inhibition or ATF2 overexpression.
- SET8 interacted with ATF2, and both were enriched at the TICAM-2 promoter, with SET8 modulating its activity.
Conclusions:
- SET8 interacts with ATF2 to regulate TICAM-2 expression, contributing to LPS-mediated microglial inflammation.
- This pathway is crucial in the pathogenesis of sepsis-associated encephalopathy.
- Targeting the SET8-ATF2-TICAM-2 axis may offer therapeutic strategies for neuroinflammation.
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