Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4.
Toll-like receptors (TLRs), which are activated by invading microorganisms or endogenous molecules, evoke immune and inflammatory responses. TLR activation is closely linked to the development of many chronic inflammatory diseases including rheumatoid arthritis. Auranofin, an Au(I) compound, is a well-known and long-used anti-rheumatic drug. However, the mechanism as to how auranofin relieves the symptom of rheumatoid arthritis has not been fully clarified. Our results demonstrated that auranofin suppressed TLR4-mediated activation of transcription factors, NF-kappaB and IRF3, and expression of COX-2, a pro-inflammatory enzyme. This suppression was well correlated with the inhibitory effect of auranofin on the homodimerization of TLR4 induced by an agonist. Furthermore, auranofin inhibited NF-kappaB activation induced by MyD88-dependent downstream signaling components of TLR4, MyD88, IKKbeta, and p65. IRF3 activation induced by MyD88-independent signaling components, TRIF and TBK1, was also downregulated by auranofin. Our results first demonstrate that auranofin suppresses the multiple steps in TLR4 signaling, especially the homodimerization of TLR4. The results suggest that the suppression of TLR4 activity by auranofin may be the molecular mechanism through which auranofin exerts anti-rheumatic activity.
Youn
Hyung S
HS
USDA, ARS, Western Human Nutrition Research Center, Department of Nutrition, University of California, Davis, CA 95616, USA. hyoun@suv.ac.kr
Lee
Joo Y
JY
Saitoh
Shin I
SI
Miyake
Kensuke
K
Hwang
Daniel H
DH
D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage; D001310:Auranofin / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006046:Gold / Q000008:administration & dosage; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D018501:Antirheumatic Agents; D004338:Drug Combinations; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D001310:Auranofin; D006046:Gold