A prototype surface-reaction-type pre-reacted glass-ionomer (S-PRG) filler containing root canal sealer (S-PRG sealer) exhibits bioactive potential by releasing multiple ions. This study explored the suppressive effects and modes of action of S-PRG sealer extracts on proinflammatory cytokine expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Expression of proinflammatory cytokines was evaluated by RT-qPCR and ELISA. Expression of phosphorylated nuclear factor-kappa B (p-NF-kB) p65 was evaluated by western blotting. S-PRG sealer extracts significantly downregulated mRNA expression levels of interleukin (IL)-1α, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells; the extracts also reduced the levels of IL-6 protein and p-NF-kB. In order to verify that Zn 2+ was responsible for downregulation of proinflammatory cytokine expression, N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) was used as a heavy metal chelator with strong affinity for Zn 2+ . These effects were mitigated by TPEN. The application of ZnCl2 reproduced the actions of S-PRG sealer extracts. These data suggest that S-PRG sealer has anti-inflammatory potential involving heavy metal ions such as Zn 2+ .