Acetaminophen down-regulates interleukin-1beta-induced nuclear factor-kappaB nuclear translocation in a human astrocytic cell line.
In previous studies performed to elucidate acetaminophen mechanism of action, we demonstrated that acetaminophen inhibits prostaglandin E2 production by interleukin (IL)-1beta-stimulated T98G human astrocytic cells, without affecting cyclooxygenase-2 enzymatic activity. As this result suggests an effect at transcriptional level, we examined whether the drug interferes with the activation of nuclear factor (NF)-kappaB and STAT3 transcription factors and with SAPK signal transducing factor. Western blot analysis of IkappaBalpha protein in the cytoplasm of IL-1beta-stimulated T98G cells and electrophoretic mobility shift assay (EMSA) on corresponding nuclear extracts indicate that acetaminophen (10-1000 microM) dose-dependently inhibits both IkappaBalpha degradation and NF-kappaB nuclear translocation. In the same cell type neither IL-1beta-dependent SAPK activation nor IL-6-induced STAT3 phosphorylation is affected by the drug. These data indicate that therapeutic concentrations of acetaminophen induce an inhibition of IL-1beta-dependent NF-kappaB nuclear translocation. The selectivity of this effect suggests the existence of an acetaminophen specific activity at transcriptional level that may be one of the mechanisms through which the drug exerts its pharmacological effects.
Mancini
Francesca
F
Pharmacology Department, ACRAF S.p.A., Piazzale della Stazione snc, 00040 Santa Palomba - Pomezia, Rome, Italy.
Landolfi
Carla
C
Muzio
Marta
M
Aquilini
Luciano
L
Soldo
Lucia
L
Coletta
Isabella
I
Guglielmotti
Angelo
A
Mantovani
Alberto
A
Pinza
Mario
M
Milanese
Claudio
C
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D000072000:NF-KappaB Inhibitor alpha; D000082:Acetaminophen; D020928:Mitogen-Activated Protein Kinases