title: Resin monomer-induced differential activation of MAP kinases and apoptosis in mouse macrophages and human pulp cells.
abstract: 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.
authors.affiliation: Department of Operative Dentistry and Periodontology, University of Regensburg, University Medical Center, Regensburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krifka
authors.forename: Christine
authors.initials: C
authors.lastname: Petzel
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Hiller
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frank
authors.forename: Claudia
authors.initials: C
authors.lastname: Bosl
authors.forename: Gianrico
authors.initials: G
authors.lastname: Spagnuolo
authors.forename: Franz-Xaver
authors.initials: FX
authors.lastname: Reichl
authors.forename: Gottfried
authors.initials: G
authors.lastname: Schmalz
authors.forename: Helmut
authors.initials: H
authors.lastname: Schweikl
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003188:Composite Resins / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003782:Dental Pulp / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011109:Polymethacrylic Acids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003188:Composite Resins; D016207:Cytokines; D008070:Lipopolysaccharides; D011109:Polymethacrylic Acids; C020946:triethylene glycol dimethacrylate; D011092:Polyethylene Glycols; D020928:Mitogen-Activated Protein Kinases