FoxO3 might be involved in the inflammatory response of human monocytes to lipopolysaccharide through regulating expression of toll like receptor 4.

Objective: Previous studies have found that forkhead box o3 S574 phosphorylation status can regulate inflammation by inducing monocytes/macrophages apoptosis, and whether it directly affects the inflammatory response of monocytes has not been demonstrated. The aim of this study was to investigate the role of forkhead box o3 in inflammatory response of monocytes against lipopolysaccharide.

Methods: THP-1 cells were used to knock down or overexpress forkhead box o3 and its mutants, and then detect the activation of inflammatory cytokines expression and activation of nuclear factor kappa B after lipopolysaccharide treatment.

Results: The present study demonstrated that lipopolysaccharide can up-regulate forkhead box o3 protein expression, especially the non-phosphorylated form at S574, in a post-transcriptional way. Knockdown of forkhead box o3 attenuated lipopolysaccharide mediated nuclear factor kappa B activation and downstream inflammatory cytokines expression. When overexpressing forkhead box o3, only non-phosphorylated S574A forkhead box o3 mutant enhanced lipopolysaccharide induced nuclear factor kappa B activation and inflammatory cytokines expression. Further studies have found that S574A forkhead box o3 may promote toll like receptor 4 expression through binding and accelerating its transcriptional activity from promoter.

Conclusion: There might be a positive feedback loop between lipopolysaccharide and forkhead box o3 in monocytes to promote the lipopolysaccharide mediated inflammatory response.