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

Wu, Hsiao-Mei; Wen, Hui-Chun; Lin, Wan-Wan

doi:10.1165/ajrcmb.27.2.4792

Cited by 56 publications

(53 citation statements)

References 35 publications

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“…Although some reports showed that proteasome inhibitors down-regulate IL-8 (83)(84)(85), others showed an increase in IL-8 expression and secretion (51)(52)(53)(54)(55). The present work reconciles these apparently conflicting reports by demonstrating that proteasome inhibition regulates IL-8 production in a time-dependent manner.…”

Section: Discussionsupporting

confidence: 69%

“…Previous studies showed that inhibition of the proteasome results in an increase in IL-8 production in other cell types (51)(52)(53)(54)(55) and that extensive oxidative stress can impair the function of the UPP (32)(33)(34)(35)(36)(37)56). To test whether oxidation-induced proteasome inactivation could be the potential mechanistic link between oxidative stress and the enhanced production of IL-8 by RPE cells, we determined the effect of oxidative stress on proteasome activity in ARPE-19 cells.…”

Section: H 2 O 2 Paraquat or A2e-mediated Photooxidation Inactivatmentioning

confidence: 99%

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Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Fernandes

Zhou

Zhang

et al. 2008

Journal of Biological Chemistry

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Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. Stress-induced overproduction of inflammatory cytokines, such as interleukin-8 (IL-8), is one of the early events of inflammation. The objective of this study was to elucidate mechanistic links between oxidative stress and overproduction of IL-8 in retinal pigment epithelial (RPE) cells. We found that exposure of RPE cells to H 2 O 2 , paraquat, or A2E-mediated photooxidation resulted in increased expression and secretion of IL-8. All of these oxidative stressors also inactivated the proteasome in RPE cells. In contrast, tert-butylhydroperoxide (TBH), a lipophilic oxidant that did not stimulate IL-8 production, also did not inactivate the proteasome. Moreover, prolonged treatment of RPE cells with proteasome-specific inhibitors recapitulated the stimulation of IL-8 production. These data suggest that oxidative inactivation of the proteasome is a potential mechanistic link between oxidative stress and up-regulation of the proinflammatory IL-8. The downstream signaling pathways that govern the production of IL-8 include NF-B and p38 MAPK. Proteasome inhibition both attenuated the activation and delayed the turnoff of NF-B, resulting in biphasic effects on the production of IL-8. Prolonged proteasome inhibition (>2 h) resulted in activation of p38 MAPK via activation of MKK3/6 and increased the production of IL-8. Chemically inhibiting the p38 MAPK blocked the proteasome inhibition-induced up-regulation of IL-8. Together, these data indicate that oxidative inactivation of the proteasome and the related activation of the p38 MAPK pathway provide a potential link between oxidative stress and overproduction of proinflammatory cytokines, such as IL-8.Oxidative stress, which refers to cellular damage caused by reactive oxygen species, has been implicated in the onset and progression of many age-related diseases, including age-related macular degeneration (AMD), 3 arthritis, atherosclerosis, and certain types of cancer (1-3). Inflammatory events are also known to participate in the pathogenesis of these age-related diseases. The activation of redox-sensitive transcription factors may be involved in triggering the expression of proinflammatory cytokines (2). However, the molecular links between oxidative stress and inflammation are not fully understood.Retina has the highest metabolic rate and oxygen consumption in the body. The high metabolic rate and oxygen consumption is usually accompanied by generation of reactive oxygen species. Chronic exposure to light could also increase the production of reactive oxygen species (1, 4). Therefore, retinal pigment epithelium (RPE) is a primary target of oxidative stress.Age-related accumulation of lipofuscin in RPE is another source of oxidative stress. Lipofuscin is a mixture of nondegradable protein-lipid aggregates derived from the ingestion of photoreceptor outer segments (5). A2E is the major fluorophore of lipofuscin and acts as a photosensitizer to generate reactive oxygen spe...

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Section: Discussionsupporting

confidence: 69%

Section: H 2 O 2 Paraquat or A2e-mediated Photooxidation Inactivatmentioning

confidence: 99%

Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Fernandes

Zhou

Zhang

et al. 2008

Journal of Biological Chemistry

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“…We used the SN50 peptide inhibitor of nuclear translocation of NF-B to dissect these responses. SN50 was selected, because it is relatively specific for NF-B (35), and proteasome inhibitors, commonly used to inhibit NF-B, also activate proinflammatory pathways such as c-Jun N-terminal kinase and AP-1 by mechanisms that have yet to be fully characterized (52,53). Only small effects of the less active NF-B control peptide SN50 M (35) were observed on pLPS-induced neutrophil survival, whereas the active SN50 inhibitor significantly prevented pLPS-induced neutrophil survival.…”

Section: Discussionmentioning

confidence: 99%

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

Sabroe

Prince

Jones

et al. 2003

The Journal of Immunology

305

290

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Neutrophil responses to commercial LPS, a dual Toll-like receptor (TLR)2 and TLR4 activator, are regulated by TLR expression, but are amplified by contaminating monocytes in routine cell preparations. Therefore, we investigated the individual roles of TLR2 and TLR4 in highly purified, monocyte-depleted neutrophil preparations, using selective ligands (TLR2, Pam3CysSerLys4 and Staphylococcus aureus peptidoglycan; TLR4, purified LPS). Activation of either TLR2 or TLR4 caused changes in adhesion molecule expression, respiratory burst (alone, and synergistically with fMLP), and IL-8 generation, which was, in part, dependent upon p38 mitogen-activated protein kinase signaling. Neutrophils also responded to Pam3CysSerLys4 and purified LPS with down-regulation of the chemokine receptor CXCR2 and, to a lesser extent, down-regulation of CXCR1. TLR4 was the principal regulator of neutrophil survival, and TLR2 signals showed relatively less efficacy in preventing constitutive apoptosis over short time courses. TLR4-mediated neutrophil survival depended upon signaling via NF-κB and mitogen-activated protein kinase cascades. Prolonged neutrophil survival required both TLR4 activation and the presence of monocytes. TLR4 activation of monocytes was associated with the release of neutrophil survival factors, which was not evident with TLR2 activation, and TLR2 activation in monocyte/neutrophil cocultures did not prevent late neutrophil apoptosis. Thus, TLRs are important regulators of neutrophil activation and survival, with distinct and separate roles for TLR2 and TLR4 in neutrophil responses. TLR4 signaling presents itself as a pharmacological target that may allow therapeutic modulation of neutrophil survival by direct and indirect mechanisms at sites of inflammation.

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“…3 The effect of proteasome inhibitors on PrP mRNA and synthetic rate first became apparent after 2-4 h of treatment, and was very marked after 18 -24 h. Our evidence suggests that the effect is related to the CMV promoter driving expression of PrP, because proteasome inhibitors did not alter levels of PrP protein or mRNA derived from the endogenous rat gene in PC12 cells, or from the mouse PrP gene (either endogenous or carried on a transgene) in cultured neurons. The mechanism underlying this unexpected effect of proteasome inhibitors could be related to stabilization of the turnover of transcription or translation factors, or to activation of signaling pathways that impinge on transcription from the CMV promoter (45)(46)(47)(48). Because the effect varied between different clones of stably transfected cells, it seems likely that the insertion site in the chromatin could also play a role.…”

Section: Discussionmentioning

confidence: 99%

Mutant PrP Is Delayed in Its Exit from the Endoplasmic Reticulum, but Neither Wild-type nor Mutant PrP Undergoes Retrotranslocation Prior to Proteasomal Degradation

Drisaldi

Stewart

Adles

et al. 2003

Journal of Biological Chemistry

212

211

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The cellular mechanisms by which prions cause neurological dysfunction are poorly understood. To address this issue, we have been using cultured cells to analyze the localization, biosynthesis, and metabolism of PrP molecules carrying mutations associated with familial prion diseases. We report here that mutant PrP molecules are delayed in their maturation to an endoglycosidase H-resistant form after biosynthetic labeling, suggesting that they are impaired in their exit from the endoplasmic reticulum (ER). However, we find that proteasome inhibitors have no effect on the maturation or turnover of either mutant or wild-type PrP molecules. Thus, in contrast to recent studies from other laboratories, our work indicates that PrP is not subject to retrotranslocation from the ER into the cytoplasm prior to degradation by the proteasome. We find that in transfected cells, but not in cultured neurons, proteasome inhibitors cause accumulation of an unglycosylated, signal peptide-bearing form of PrP on the cytoplasmic face of the ER membrane. Thus, under conditions of elevated expression, a small fraction of PrP chains is not translocated into the ER lumen during synthesis, and is rapidly degraded in the cytoplasm by the proteasome. Finally, we report a previously unappreciated artifact caused by treatment of cells with proteasome inhibitors: an increase in PrP mRNA level and synthetic rate when the protein is expressed from a vector containing a viral promoter. We suggest that this phenomenon may explain some of the dramatic effects of proteasome inhibitors observed in other studies. Our results clarify the role of the proteasome in the cell biology of PrP, and suggest reasonable hypotheses for the molecular pathology of inherited prion diseases.

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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

Cited by 56 publications

References 35 publications

Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Selective Roles for Toll-Like Receptor (TLR)2 and TLR4 in the Regulation of Neutrophil Activation and Life Span

Mutant PrP Is Delayed in Its Exit from the Endoplasmic Reticulum, but Neither Wild-type nor Mutant PrP Undergoes Retrotranslocation Prior to Proteasomal Degradation

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