title: Antipyretic analgesic drugs have different mechanisms for regulation of the expression of inducible nitric oxide synthase in hepatocytes and macrophages.
abstract: Antipyretic analgesic drugs (including non-steroidal anti-inflammatory drugs) inhibit cyclooxygenase-2 and inducible nitric oxide synthase (iNOS), resulting in decreases of the proinflammatory mediators prostaglandin E2 and nitric oxide (NO), respectively. Both mediators are regulated by nuclear factor-kappa B (NF-κB), a key transcription factor in inflammation. Few reports have compared the efficacy and potency of anti-inflammatory drugs as NO inhibitors. In our study, we examined the effects of four popular antipyretic analgesic drugs on NO production induced in hepatocytes and macrophages. Mouse RAW264.7 macrophages treated with bacterial lipopolysaccharide showed the highest efficacy with regard to NO production; aspirin, loxoprofen, ibuprofen, and acetaminophen dose-dependently suppressed NO induction. Ibuprofen showed the highest potency in suppressing the induced production of NO. In rat hepatocytes, all the drugs inhibited interleukin 1β-induced NO production and ibuprofen and loxoprofen inhibited NO induction effectively. Unexpectedly, the potency of NO suppression of each drug in hepatocytes did not always correlate with that observed in RAW264.7 cells. Microarray analyses of mRNA expression in hepatocytes revealed that the effects of the four antipyretic analgesic drugs modulated the NF-κB signaling pathway in a similar manner to the regulation of the expression of genes associated with inflammation, including the iNOS gene. However, the affected signal-transducing molecules in the NF-κB pathway were different for each drug. Therefore, antipyretic analgesic drugs may decrease NO production by modulating the NF-κB pathway in different ways, which could confer different efficacies and potencies with regard to their anti-inflammatory effects.
authors.affiliation: Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan; Research and Development Headquarters, Lion Corporation, Odawara, Kanagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inaba
authors.affiliation: Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Yoshigai
authors.affiliation: Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan; Graduate School of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okuyama
authors.affiliation: Research and Development Headquarters, Lion Corporation, Odawara, Kanagawa, Japan; Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Murakoshi
authors.affiliation: Research and Development Headquarters, Lion Corporation, Odawara, Kanagawa, Japan; Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Keikichi
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto, Japan; Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Hoyoku
authors.initials: H
authors.lastname: Nishino
authors.affiliation: Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan. Electronic address: nishizaw@sk.ritsumei.ac.jp.
authors.forename: Mikio
authors.initials: M
authors.lastname: Nishizawa
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D058633:Antipyretics / Q000494:pharmacology*; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000700:Analgesics; D058633:Antipyretics; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Acetaminophen; Antisense transcript; Hepatocyte; Inducible nitric oxide synthase; Macrophage; NF-κB; NSAID; Nitric oxide