Auranofin inhibits interleukin-1β-induced transcript of cyclooxygenase-2 on cultured human synoviocytes

Yamada, Ryoji; Sano, Hajime; Hla, Timothy; Hashiramoto, Akira; Fukui, Wakako; Miyazaki, Shôzo; Kohno, Masataka; Tsubouchi, Yasunori; Kusaka, Yoshiaki; Kondo, Motoharu

doi:10.1016/s0014-2999(99)00707-4

Cited by 26 publications

(22 citation statements)

References 45 publications

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“…1A and B). These results were consistent with the findings demonstrated in our previous study [13].The inhibitory effect of auranofin on ICAM-1 expression stimulated by proinflammatory cytokines Auranofin exerts the pharmacological activity on anti-inflammation by inhibiting NF-κB activation [19,25]. We con- firmed the effect of this compound on expression of ICAM-1 which is a pivotal target gene of transcription factor NF-κB.…”

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confidence: 92%

Auranofin Downregulates Nuclear Factor-κB Activation via Nrf2-Independent Mechanism

Kim¹,

Park²,

Kim³

2010

Journal of Life Science

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Transcription factors Nrf2 and NF-kB are important regulators of the innate immune response, and their cross-talks in inflammation have been reported. Previously, we demonstrated that gold(I)-compound auranofin, an inhibitor of NF-kB signal, induced Nrf2 activation in human synovial cells and monocytic cells. To investigate whether the Nrf2 activation is involved in the mechanism of the auranofin-attenuated NF-kB signaling, we examined the effects of Nrf2 knockdown on NF-kB activation using rheumatic synovial cells. When the cells were transfected with a specific siRNA for Nrf2, the gene expression was perfectly blocked. However, the Nrf2 knockdown did not cancel the suppressive effect of auranofin on TNF-α-induced IkB-a degradation. Treatment with a specific siRNA for HO-1, which is a target of Nrf2 and plays a role in anti-inflammation, also did not affect the blocking activity of auranofin on IkB-a degradation. In addition, auranofin-inhibited ICAM-1 expression was not restored by Nrf2 knockdown. These findings indicate that the activated Nrf2 and HO-1 are not associated with the suppressive action of auranofin on the pro-inflammatory cytokines-stimulated NF-kB activation. This suggests that Nrf2/HO-1 and NF-kB signals, which are regulated by auranofin, participate in the anti-inflammatory action of auranofin via independent pathways in rheumatic synovial cells.Key words : Auranofin, nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor-κB (NF-κB), intercellular adhesion molecule-1 (ICAM-1) † Present address Introduction Auranofin (2, 3, 4, 6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S-[triethylphosphine] gold) is a thiol-reactive gold(I) compound that has been used for the treatment of rheumatoid arthritis for a long time [1]. The drug possesses the inhibitory activity for nuclear factor κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), and toll-like receptor 4 [6,12,26]. Recently, we reported a novel anticancer activity of auranofin by demonstrating that auranofin induced apoptosis and promoted all-trans retinoic acid-mediated differentiation of acute promyelocytic leukemia cells [11,20,21]. Therefore, the gold(I) compounds including auranofin have been studied for therapeutic application to inflammation and cancer [3,4,19,22,24].In the mechanisms on anti-inflammatory and antirheumatic actions of auranofin, the inhibitory effect on NF-κB signal pathway has been well known. The thiol-reactive auranofin modifies Cys-179 in beta subunit of inhibitory κB kinase (IKK), which results in the blockade of inhibitory κB-α (IκB-α) phosphorylation and degradation [6,7]. Consequently, auranofin attenuates the transcriptional activity of NF-κB and downregulates the expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).Heme oxygenase-1 (HO-1), which suppresses an inflammatory response, is also associated with the pharmacological property of auranofin in rheumatoid arthritis [14,16]. In the previous study, we ...

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confidence: 92%

Auranofin Downregulates Nuclear Factor-κB Activation via Nrf2-Independent Mechanism

Kim¹,

Park²,

Kim³

2010

Journal of Life Science

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“…Western blot analysis was performed to determine PPAR-γ protein expression as described previously (42). Total protein extract from patients with RA (n = 5) and fat tissue was analyzed on blots incubated for 1 hour at room temperature with 1:200 dilution of goat anti-PPAR-γ antibody (Santa Cruz Biotechnology Inc.), washed, and subsequently incubated for 1 hour at room temperature with horseradish peroxidase-linked rabbit anti-goat IgG (1:1500 dilution; EY Laboratories Inc., San Mateo, California, USA).…”

Section: Methodsmentioning

confidence: 99%

15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

Kawahito¹,

Kondo²,

Tsubouchi³

et al. 2000

J. Clin. Invest.

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“…Cell lysates were then centrifuged at 13,000g for 15 min and supernatants were harvested and boiled at 95°C. We performed Western blot analysis to determine the PPAR-␥ protein expression as previously described (14). Aliquots of protein were then separated by 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred onto a polyvinylidene difluoride (PVDF) membrane (ATTO, Tokyo, Japan).…”

Section: Rt-pcrmentioning

confidence: 99%

Expression of Peroxisome Proliferator-Activated Receptor γ in Renal Cell Carcinoma and Growth Inhibition by Its Agonists

Inoue

Kawahito

Tsubouchi

et al. 2001

Biochemical and Biophysical Research Communications

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Auranofin inhibits interleukin-1β-induced transcript of cyclooxygenase-2 on cultured human synoviocytes

Cited by 26 publications

References 45 publications

Auranofin Downregulates Nuclear Factor-κB Activation via Nrf2-Independent Mechanism

Auranofin Downregulates Nuclear Factor-κB Activation via Nrf2-Independent Mechanism

15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

Expression of Peroxisome Proliferator-Activated Receptor γ in Renal Cell Carcinoma and Growth Inhibition by Its Agonists

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