A phenolic acid phenethyl urea compound inhibits lipopolysaccharide-induced production of nitric oxide and pro-inflammatory cytokines in cell culture.
We previously used the Curtius rearrangement to synthesize various phenolic acid phenethyl urea compounds from phenolic acids and demonstrated their beneficial anti-oxidant and anti-cancer effects. Here, we investigated the effects of one of these synthetic compounds, (E)-1-(3,4-dihydroxystyryl)-3-(4-hydroxyphenethyl)urea (DSHP-U), on nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, and cytokine secretion in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. DSHP-U suppressed LPS-induced NO production and iNOS expression at a concentration of 50 microM and inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase. Inhibitors of phosphorylated (p)-ERK and p-p38, but not of p-JNK, reduced LPS-stimulated NO production. DSHP-U also prevented the nuclear translocation of the Rel A (p65) subunit and DNA-NF-kappaB binding by suppressing IkappaBalpha phosphorylation and by the degradation of IkappaBalpha in LPS-stimulated cells. Furthermore, DSHP-U decreased the production of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in LPS-treated macrophages. However, the LPS-stimulated expression of LPS receptors, such as Toll-like receptor 4, myeloid differentiation factor-2, and CD14, was unchanged after DSHP-U treatment at significantly high levels. Our data suggest that DSHP-U blocks NO and inflammatory cytokine production in LPS-stimulated macrophages and that these effects are mainly mediated through the inhibition of the ERK/p38- and NF-kappaB signaling pathways.
Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, South Korea,
Jung-Min
JM
Hwang
Ji-Yeon
JY
Yu
Young-Oh
YO
Jang
Beom-Tae
BT
Kim
Ki-Jun
KJ
Hwang
Young-Mi
YM
Jeon
Jeong-Chae
JC
Lee
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010519:Periodontium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013343:Styrenes / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C550461:1-(3,4-dihydroxystyryl)-3-(4-hydroxyphenethyl)urea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013343:Styrenes; D009569:Nitric Oxide; D014508:Urea; D052247:Nitric Oxide Synthase Type II