Proteasome inhibitor MG-132 enhances the expression of interleukin-6 in human umbilical vein endothelial cells: Involvement of MAP/ERK kinase.
Interleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in inflammatory reactions. We have addressed the possible regulation of IL-6 expression by the ubiquitin-protease system in human umbilical vein endothelial cells. Cultured endothelial cells were treated with MG-132, a protease inhibitor, and the levels of IL-6 mRNA and protein were measured by reverse transcription-PCR and ELISA. MG-132 increased the expression of IL-6 mRNA and protein;and this effect was abolished by the pretreatment of the cells with U0126, an inhibitor of MAP or ERK kinases (MEK 1/2). MG-132 treatment was also found to enhance the level of phosphorylated MEK 1/2. Treatment of the cells with actinomycin D inhibited IL-6 expression in response to MG-132, suggesting the transcriptional upregulation of IL-6 under proteasomal inhibition. We conclude that a protease inhibitor MG-132 upregulates IL-6 expression in vascular endothelial cells, at least in part, through the activation of MEK 1/2.
Shibata
Takeo
T
Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki, Japan.
Imaizumi
Tadaatsu
T
Tamo
Wakako
W
Matsumiya
Tomoh
T
Kumagai
Mika
M
Cui
Xue-Fan
XF
Yoshida
Hidemi
H
Takaya
Shun-Ichi
S
Fukuda
Ikuo
I
Satoh
Kei
K
D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000201:enzymology / Q000276:immunology*
D002070:Butadienes; D015853:Cysteine Proteinase Inhibitors; D020672:I-kappa B Proteins; D015850:Interleukin-6; D007976:Leupeptins; D009097:Multienzyme Complexes; D009570:Nitriles; C113580:U 0126; D003609:Dactinomycin; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde