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Proteasome Inhibitors Stimulate Interleukin-8 Expression via Ras and Apoptosis Signal-Regulating Kinase-dependent Extracellular Signal-Related Kinase and c-Jun N-Terminal Kinase Activation

Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

Address correspondence to: Wan Wan Lin, Ph.D., Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. E-mail: wwl{at}ha.mc.ntu.edu.tw

In this study, we investigated the effects of proteasome inhibibors (MG132 and lactacystin) on interleukin (IL)-8 induction. In human epithelial A549 cells, MG132 and lactacystin induced IL-8 release within the range of 0.1–30 µM. The effect of MG132 resulted from IL-8 gene transcription and was blocked by PD 98059, but was unaffected by GF109203X, Ro 31–8220, or SB 203580. Mutational analysis of the 5' flanking region of the IL-8 gene revealed that activator protein (AP)-1–binding element, but not that element responsive to nuclear factor (NF)–IL-6 or NF-B, was necessary for MG132 stimulation. Consistent with this, MG132 and lactacystin increased the DNA-binding and reporter activities of AP-1, but reduced cytokine-elicited B activation. Moreover, AP-1 stimulation was associated with increased extracellular signal-related kinase (ERK), mitogen-activated protein/ERK kinase (MEK), and c-Jun N-terminal kinase (JNK) phosphorylation, whereas IL-8 activity was sensitive to the dominant-negative mutants of JNK1, JNK2, SEK, ASK, ERK2, and Ras, but not those of MEKK1, TAK, and p38 mitogen-activated protein kinase. In addition, activations of the IL-8 gene and AP-1 by MG132 and lactacystin were inhibited by GSH and NAC. Herein we present a novel action of proteasome inhibitors, possibly through ROS production, of targeting the upstream signaling molecules, ERK and JNK, which leads to AP-1 activation and IL-8 gene expression.

Abbreviations: activator protein 1, AP-1 • Dulbecco's modified Eagle's medium, DMEM • enhanced chemiluminescence, ECL • enzyme-linked immunosorbent assay, ELISA • electrophoretic mobility shift assay, EMSA • extracellular signal-related kinase, ERK • fetal bovine serum, FBS • fluorescein isothiocyanate, FITC • glutathione, GSH • interleukin, IL • c-Jun N-terminal kinase, JNK • mitogen-activated protein kinase, MAPK • mitogen-activated protein/ERK kinase, MEK • carbobenzoxy-Leu-Leu-leucinal, MG132 • N-acetylcysteine, NAC • nuclear factor, NF • reactive oxygen species, ROS • reverse transcriptase–polymerase chain reaction, RT-PCR • Tris-buffered saline containing 0.1% Tween 20, TBST • tumor necrosis factor-, TNF-

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