title: Acetaminophen and lipopolysaccharide act in synergy for the production of pro-inflammatory cytokines in murine RAW264.7 macrophages.
abstract: There is extensive evidence that pro-inflammatory cytokines produced by macrophages are involved in toxicity induced by drugs such as acetaminophen (APAP). We investigated the effect of subtoxic concentrations of acetaminophen in conjunction with bacterial lipopolysaccharide (LPS) on the expression of the pro-inflammatory cytokines TNFalpha and IL-1beta using the mouse macrophage cell line RAW264.7 as a model. APAP alone induced in a dose-dependent manner the production of TNFalpha and IL-1beta in this cell line. When LPS was added to APAP-treated cells, the increase in TNFalpha and IL-1beta production observed was higher than the sum of cytokine amounts produced with each agent alone, suggesting a synergistic mechanism. Moreover, we found that p38MAPK, JNK, and ERK were activated by APAP or LPS alone or in association. In our model, the NFkappaB signaling pathway was not involved in cytokine production induced by APAP. When inhibiting MAPKs using pharmacological inhibitors, we showed that p38MAPK inhibition abrogated the synergistic effect of APAP and LPS found for TNFalpha production but not for IL-1beta production. JNK and ERK have comparable roles in the production of the cytokines. Furafylline, a CYP1A inhibitor, and indomethacin, a PGHS inhibitor, exhibited a significant inhibitory effect on TNFalpha and IL-1beta production induced by the APAP and LPS combination. This work suggests that in macrophages, APAP and LPS can synergistically provoke the induction of pro-inflammatory cytokines, an effect involving the MAPK pathway and APAP bioactivation by CYP and PGHS.
authors: Sanofi-Aventis Drug Safety Evaluation, Centre de Recherche de Vitry / Alfortville - Evry, Vitry sur Seine, Paris, France.
authors: Sandrine
authors: S
authors: Lacour
authors: Diane
authors: D
authors: Antonios
authors: Jean-Charles
authors: JC
authors: Gautier
authors: Marc
authors: M
authors: Pallardy
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000873:Anthracenes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D000082:Acetaminophen; D013806:Theophylline; C050131:furafylline; D011451:Prostaglandin-Endoperoxide Synthases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D007213:Indomethacin