Phenethyl isothiocyanate suppresses nitric oxide production via inhibition of phosphoinositide 3-kinase/Akt-induced IFN-gamma secretion in LPS-activated peritoneal macrophages.
Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, is well known to have versatile physiological activities, including chemopreventive effects. On the other hand, its anti-inflammatory effects are poorly reported. Nitric oxide (NO) is associated with a wide variety of inflammatory diseases. In this study, we investigated the effects of PEITC on NO production in LPS-activated peritoneal macrophages from ICR mice. The signaling pathway of LPS-induced NO production was examined using neutralizing antibodies [anti-interferon (IFN)-gamma and anti-interleukin (IL-12)] and specific protein kinase inhibitors, as well as others. The activity of PEITC toward NOx production was assessed in mice that received LPS via intraperitoneal administration. The neutralizing antibody of anti-IFN-gamma, but not anti-IL-12, suppressed LPS-induced NO production by 90%. LY294002, a specific inhibitor of phosphoinositide-3-kinase, suppressed Akt and IFN-gamma mRNA expression up-regulated by LPS, whereas PEITC exhibited a similar inhibition profile. Furthermore, oral administration of PEITC significantly suppressed the serum concentration of NOx in ICR mice. Our results suggest that PEITC suppresses LPS-induced NO production via inhibition of Akt activation and the resultant decrease in expression of IFN-gamma. This is one of the first reports to demonstrate a marked anti-inflammatory effect of PEITC following its oral administration.
Okubo
Toru
T
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Washida
Kazuto
K
Murakami
Akira
A
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D057134:Antibodies, Neutralizing; D007371:Interferon-gamma; D018664:Interleukin-12; D017879:Isothiocyanates; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C058305:phenethyl isothiocyanate; C496317:Nos2 protein, mouse