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.
Keywords: ATF2; SET8; inflammation; microglia; microglie.