Auranofin blocks interleukin‐6 signalling by inhibiting phosphorylation of JAK1 and STAT3

Abstract

SummaryAuranofin (AF) is a sulphur-containing gold compound. Because of its anti-inflammatory and immunosuppressive activities, AF has been widely used for the therapeutic treatment of rheumatoid arthritis. However, little is known about its mechanism of action. To elucidate the molecular mechanism underlying the anti-inflammatory effect of AF, we studied the effects of AF on cellular responses to interleukin-6 (IL-6). In HepG2 human hepatoma cells, AF markedly inhibited IL-6-induced phosphorylation of janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) and STAT3 translocation into the nucleus. Consistent with this, AF diminished IL-6-induced production of the acutephase proteins, haptoglobin, fibrinogen, C3 complement and a 1 -acid glycoprotein, and gene expression of vascular endothelial growth factor, all of whose transcriptional activities are regulated by STAT3. The inhibitory activity of AF on STAT3 phosphorylation was also demonstrated in primary cells, i.e. fibroblast-like synoviocytes from rheumatoid arthritis patients, human umbilical vein endothelial cells and rat astrocytes. Auranofin-mediated inhibition of STAT3 phosphorylation was recovered by pretreatment with antioxidants containing thiol groups. These findings suggest that the anti-inflammatory action of AF is associated with a blockade of JAK1/STAT3 signalling. Thiol-group-reactive proteins may be involved in AF-induced suppression of JAK1/STAT3 phosphorylation.

STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

“…36 Mutant cases also had a higher prevalence of concurrent AIHA; again, STAT3 constitutive activation might be responsible for apoptotic-resistant autoreactive T-cell clones. 37 In contrast, no mutation was found in 7 patients with CLPD-NKs or T-LGL and PRCA, where a similar line of argument involving autoreactive apoptotic-resistant immunity could be followed. Further studies are needed to address this apparent controversy; nevertheless, STAT3 SH2 domain-mutated…”

Effects of phonophoresis with gold nanoparticles on oxidative stress parameters in a traumatic muscle injury model

“…Colloidal gold and some of the compounds have recognized therapeutic properties, especially for the treatment of inflammatory and arthritic processes (Kim et al, 2007). Several studies performed in our group using phonophoresis and/or iontophoresis with topic application of GNP for treating muscle and tendon injuries in rats show promise and indicate the possibility of use this new therapy in the treatment of these diseases in humans (Freitas et al, 2007(Freitas et al, , 2010Silveira et al, 2010Silveira et al, , 2012Dohnert et al, 2012;Engelmann et al, 2012;Victor et al, 2012).…”

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“…An electrode covered with a layer of GNPs has a much higher surface roughness and larger surface area which lead to higher currents. Another application of gold compounds is as an antiinflammatory agent due to their ability to inhibit expression of NF-kappa B and subsequent inflammatory reactions [116][117][118] .…”