Absence of nuclear factor kappaB inhibition by NSAIDs in hepatocytes.
Stimulation of fetal hepatocytes with proinflammatory cytokines and lipopolysaccharide promotes the expression of cyclooxygenase-2 (COX-2) and nitric oxide synthase-2 (NOS-2), whereas the hepatoma cell line HepG2 exhibits a behavior similar to that described for adult hepatocytes and only expresses NOS-2. The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the inflammatory onset was analyzed in these cells since in addition to the inhibition of cyclooxygenase activity, these drugs interfere with other signaling pathways related with the inflammatory response. Inhibition of nuclear factor kappaB (NF-kappaB) activation by aspirin and salicylate has been described in many cells. However, incubation of hepatic cells with salicylate, aspirin, indomethacin, ibuprofen, or 5,5-dimethyl-3(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a fluorinated derivative of rofecoxib, failed to impair IkappaB kinase activity, the processing of NF-kappaB, and the expression of NF-kappaB-dependent genes, such as NOS-2. Moreover, selective COX-2 inhibitors did not promote apoptosis in hepatocytes under inflammatory conditions, suggesting that prostaglandins are not required to maintain cell viability. In conclusion, these data indicate that hepatocytes are not sensitive to NF-kappaB inhibition by NSAIDs and that these drugs, especially the COX-2 selective inhibitors, do not alter cell viability.
Callejas
Nuria A
NA
Instituto de Bioquímica, Centro Mixto CSIC-UCM, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Casado
Marta
M
Boscá
Lisardo
L
Martín-Sanz
Paloma
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D005333:Fetus; D006367:HeLa Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D012459:Salicylates; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin