Proteasome inhibitors stimulate activator protein-1 pathway via reactive oxygen species production.
In this report we explored the effects of proteasome inhibitors (MG132, aLLN, lactacystin and MG262) on interleukin-8 (IL-8) induction. In HEK293 cells, proteasome inhibitors could concentration-dependently increase IL-8 promoter and activator protein-1 (AP-1) activities, but inhibited nuclear factor (NF)-kappa B activation induced by cytokines. The stimulating effects on IL-8 promoter and AP-1 were reduced by N-acetylcysteine, glutathione, diphenyleneiodonium, rotenone and antimycin A. Fluorescent analysis using 2',7'-dichlorodihydrofluorescin diacetate further confirmed the abilities of proteasome inhibitors to induce reactive oxygen species (ROS) production. These results suggest that ROS production by proteasome inhibitors leads to AP-1 activation, which in the absence of NF-kappa B activation still transactivates IL-8 gene expression.
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hsiao-Mei
HM
Wu
Kwan-Hwa
KH
Chi
Wan-Wan
WW
Lin
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D007976:Leupeptins / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection
D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D016209:Interleukin-8; D007976:Leupeptins; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; C067713:lactacystin; D008156:Luciferases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine