Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and STAT3.
Auranofin (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 acute-phase proteins, haptoglobin, fibrinogen, C3 complement and alpha(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.
Kim
Nam-Hoon
NH
Department of Natural Sciences, College of Medicine, The Catholic Unviersity of Korea, Socho-Gu, Seoul, South Korea.
Lee
Mun-Yong
MY
Park
Seon-Joo
SJ
Choi
Jeong-Sun
JS
Oh
Mi-Kyung
MK
Kim
In-Sook
IS
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000187:drug effects; D001310:Auranofin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D053613:Janus Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
D000209:Acute-Phase Proteins; D018501:Antirheumatic Agents; D001310:Auranofin; D015850:Interleukin-6; D053613:Janus Kinase 1; D050796:STAT3 Transcription Factor; D013438:Sulfhydryl Compounds; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors