Suppression of IL-8 gene expression by radicicol is mediated through the inhibition of ERK1/2 and p38 signaling and negative regulation of NF-kappaB and AP-1.
We show that radicicol, an anti-fungal agent, inhibits interleukin-8 (IL-8) production by the human monocyte line THP-1 in response to phorbol-12-myristate-13-acetate/lipopolysaccharide (PMA/LPS). IL-8 is a potent chemokine and needs for an optimal immune response--such as inflammation by activation of neutrophils. The decrease in PMA/LPS-induced IL-8 mRNA expression was demonstrated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Since the promoter in IL-8 gene contains binding motifs for NF-KB, AP-1. and NF-IL6, which appear to be important in IL-8 induction, the effects of radicicol on the activation of these transcription factors were examined. Treatment of radicicol to THP-1 cells produced a strong inhibition of NF-KB and AP-1, while NF-IL6 was not significantly affected by radicicol. Western blot analysis showed that radicicol inhibited the phosphorylation and phosphotransferase activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38. PD98059 and SB203580, known as a specific inhibitor of MEKI and p38 kinase, respectively, inhibited IL-8 gene expression showing that both of the kinase pathways are involved in IL-8 regulation in human monocytes. Collectively, this series of experiments indicates that radicicol inhibits IL-8 gene expression by blocking ERK1/2 and p38 signaling.
Na
Y J
YJ
Korea Advanced Institute of Science and Technology, Yusong, Taejon, South Korea.
Jeon
Y J
YJ
Suh
J H
JH
Kang
J S
JS
Yang
K H
KH
Kim
H M
HM
D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003864:Depression, Chemical; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D007202:Indicators and Reagents; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D007783:Lactones / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D018942:Macrolides; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011233:Precipitin Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D016209:Interleukin-8; D007783:Lactones; D008070:Lipopolysaccharides; D018942:Macrolides; D016328:NF-kappa B; D010835:Phytohemagglutinins; D018808:Transcription Factor AP-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C035359:monorden