Triethylene glycol dimethacrylate (
TEGDMA) is a resin monomer which is released from polymerized dental composite materials. It induced apoptosis in various target cells or inhibition of LPS-induced
cytokine production in cells of the immune system after prolonged exposure. In these tissues,
mitogen-activated protein kinases (MAPK) regulate signal transduction pathways that support cell survival and
cytokine synthesis. The time-dependent regulation of MAPK as well as their linkage to the induction of apoptosis and
cytokine release under the influence of resin monomers is unknown. It was the aim of the present study to investigate the kinetics of the up- or down-regulation of the
MAPK p38, JNK, and ERK1/2, the induction of apoptosis and
cytokine release in RAW264.7 mouse macrophages and human pulp-derived cells. ERK1/2, p38 and JNK were differentially activated by phosphorylation in the presence of
lipopolysaccharide (0.1 microg/ml; LPS), a known inducer of MAPK activity, and
TEGDMA (3 mM) as detected by Western blotting. In macrophages, ERK1/2 was activated about 6-fold by LPS, while no activation was observed in the presence of
TEGDMA after 15 and 30 min. A slight activation of p38 was detected in cell cultures after short exposure to
TEGDMA (30 min), but activated JNK was identified after LPS stimulation only. After a long 24 h exposure period, ERK1/2 and p38 were strongly activated by LPS, a combination of LPS/
TEGDMA, and
TEGDMA alone (15-20-fold). In human pulp-derived cells, ERK1/2 was phosphorylated after exposure to
TEGDMA up to 2 h, and sustained activation of ERK1/2 as well as p38 (12-15-fold) was detected after prolonged exposure for 24 h. The LPS-induced, time-related increase in the secretion of the pro-inflammatory
cytokines tumor necrosis factor-alpha (
TNF-alpha) and
interleukin-6 (IL-6) as well as the anti-inflammatory
IL-10 was instantaneously inhibited by
TEGDMA in mouse macrophages. In parallel, the percentage of cells in macrophage cultures in the stage of apoptosis and
necrosis increased with exposure period. Yet, in contrast to the inhibition of
cytokine release, apoptosis and
necrosis caused by LPS and
TEGDMA was a late response in both mouse macrophages and human pulp-derived cells. From these data it appears as if MAPK activation, inhibition of
cytokine release and the induction of apoptosis and
necrosis by
TEGDMA are tightly related. The direct causal correlation of these phenomena, however, requires further investigation.