Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-kappa B.

Griscavage, Jeanette M.; Wilk, Sherwin; Ignarro, Louis J.

doi:10.1073/pnas.93.8.3308

Cited by 245 publications

(144 citation statements)

References 36 publications

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“…According to this model, the expression of iNOS is regulated by a combination of LPS-and IFN-induced transcription factors. One aspect of this model that we have previously examined is the necessary role of NF-B for the induction of iNOS in LPS-treated RAW macrophages (38). In the present study, we sought to confirm the role of endogenous IFN-␤ as an autocrine/paracrine activator of iNOS expression, and to determine the timing of downstream events, including activation of the JAK/STAT and IRF signaling pathways, iNOS transcription and translation, and ultimately NO generation.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-induced Expression of Interferon-β Mediates the Timing of Inducible Nitric-oxide Synthase Induction in RAW 264.7 Macrophages

Jacobs

Ignarro

2001

Journal of Biological Chemistry

187

139

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The production of nitric oxide by macrophages has been implicated as a host defense mechanism against microbial pathogens and tumor cells. Recent reports have implicated interferon-␣/␤ (IFN-␣/␤) as an autocrine/paracrine signal critical for the induction of murine iNOS. In this report we have systematically investigated the role of IFN-␤ in the induction of iNOS in the murine macrophage cell line, RAW 264.7. First, we demonstrate that IFN-␤ expression is highly up-regulated, and is secreted in response to lipopolysaccharide (LPS). Treatment of RAW macrophages with LPS results in a time-dependent phosphorylation of STAT-1 on both tyrosine residue 701 (Tyr-701) and serine residue 727 (Ser-727) that is consistent with the timing of endogenous IFN-␤ expression. LPS also induces interferon regulatory factor-1 expression with similar kinetics. We further demonstrate that exogenous IFN-␤ accelerates the induction of iNOS by LPS. The acceleration of iNOS induction is observed at the levels of transcription, protein expression, and NO formation. Accordingly, we propose that the cytokine environment of macrophages may determine the rate and magnitude of nitric oxide production, thereby regulating the cytotoxic response to pathogen challenge. Activated macrophages produce nitric oxide (NO), 1 a free radical species that mediates cytotoxic and cytostatic effects against pathogenic microbes and tumor cells (1-3). The enzyme responsible for the production of NO by macrophages is the inducible isoform of nitric-oxide synthase (iNOS), which catalyzes the oxidation of one of the equivalent guanidino nitrogens of arginine to form NO and citrulline (4). Compared with the neuronal and endothelial isoforms of NOS (nNOS and eNOS, respectively), iNOS generates high concentrations of NO, which accounts for the cytotoxic and cytostatic effects of NO on target cells (5). The regulation of NO production by iNOS has been extensively studied in murine macrophages, and occurs primarily at the level of transcription. The gene encoding iNOS is transcriptionally silent, but is dramatically induced by bacterial lipopolysaccharide (LPS). LPS activates Toll-like receptordependent signaling pathways in macrophages, including the transcription factor, NF-B (6). However, maximal induction is not achieved by LPS alone. The induction of iNOS by LPS can be synergized by the addition of specific cytokines, including tumor necrosis factor-␣, interleukin-1␤, and interferon-␥ (IFN-␥) (7). This synergy is reflected in the promoter region of the murine iNOS gene, which contains oligonucleotide motifs for the binding of both LPS-and several cytokine-induced transcription factors (8).Both type I (IFN-␣/␤) and type II (IFN-␥) interferons mediate the induction of target genes via the activation of the JAK-STAT signaling pathway (9). Signal transducer and activator of transcription (STAT) proteins are a family of transcriptional activators that interact with IFN receptors and associated Janus kinase (JAK) proteins. The activation of STAT proteins is regulated by p...

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-induced Expression of Interferon-β Mediates the Timing of Inducible Nitric-oxide Synthase Induction in RAW 264.7 Macrophages

Jacobs

Ignarro

2001

Journal of Biological Chemistry

187

139

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“…Sulfasalazine has been reported to inhibit NF-B activation by interfering with phosphorylation of I B␣ (31), whereas calpain inhibitor I inhibits proteosomal degradation of I B (32). Both agents inhibited HRV-16-induced activation of NF-B, preventing the formation of complexes with the oligonucleotides derived from both the IL-6 and IL-8 gene promoter sequences.…”

Section: Discussionmentioning

confidence: 99%

Role of NF-κB in Cytokine Production Induced from Human Airway Epithelial Cells by Rhinovirus Infection

Kim

Sanders

Siekierski³

et al. 2000

The Journal of Immunology

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Infection of human epithelial cells with human rhinovirus (HRV)-16 induces rapid production of several proinflammatory cytokines, including IL-8, IL-6, and GM-CSF. We evaluated the role of NF-κB in HRV-16-induced IL-8 and IL-6 production by EMSA using oligonucleotides corresponding to the binding sites for NF-κB in the IL-6 and IL-8 gene promoters. Consistent with the rapid induction of mRNA for IL-8 and IL-6, maximal NF-κB binding to both oligonucleotides was detected at 30 min after infection. NF-κB complexes contained p65 and p50, but not c-Rel. The IL-8 oligonucleotide bound recombinant p50 with only about one-tenth the efficiency of the IL-6 oligonucleotide, even though epithelial cells produced more IL-8 protein than IL-6. Neither the potent glucocorticoid, budesonide (10−7 M), nor a NO donor inhibited NF-κB binding to either cytokine promoter or induction of mRNA for either IL-8 or IL-6. Sulfasalazine and calpain inhibitor I, inhibitors of NF-κB activation, blocked HRV-16-induced formation of NF-κB complexes with oligonucleotides from both cytokines, but did not inhibit mRNA induction for either cytokine. By contrast, sulfasalazine clearly inhibited HRV-16 induction of mRNA for GM-CSF in the same cells. Thus, HRV-16 induces epithelial expression of IL-8 and IL-6 by an NF-κB-independent pathway, whereas induction of GM-CSF is at least partially dependent upon NF-κB activation.

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“…It has been proposed that this cytosolic protease complex selectively degrades intracellular proteins and may contribute to the processing of antigens presented by major histocompatibility complex (MHC) class I molecules [41,60,61]. Furthermore, it has been suggested that it may be involved in the regulation of nitric oxide synthase expression [62]. Our results imply that the expression of powerful biological mediators such as TNF and IL-1␤ is regulated by a specific proteolytic system, the proteasome, representing one of the critical steps of control.…”

Section: Discussionmentioning

confidence: 99%

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

Haas

Page

et al. 1998

Journal of Leukocyte Biology

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Abstract:We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-B (NF-B). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of I B-␣ and -␤, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-B binding activity and NF-B transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1␤ (IL-1␤), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of I B-␣ and -␤, efficiently blocked the production of TNF and, to a lesser extent, IL-1␤, whereas that of IL-8 was not inhibited. The expression of NF-B-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

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Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-kappa B.

Cited by 245 publications

References 36 publications

Lipopolysaccharide-induced Expression of Interferon-β Mediates the Timing of Inducible Nitric-oxide Synthase Induction in RAW 264.7 Macrophages

Lipopolysaccharide-induced Expression of Interferon-β Mediates the Timing of Inducible Nitric-oxide Synthase Induction in RAW 264.7 Macrophages

Role of NF-κB in Cytokine Production Induced from Human Airway Epithelial Cells by Rhinovirus Infection

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

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