Diacerhein and rhein prevent interleukin-1β-induced nuclear factor-κB activation by inhibiting the degradation of inhibitor κB-α

Diacerhein and them are anthraquinone compounds that ameliorate the course of osteoarthritis. Recent reports also suggest that these compounds may have antiinflammatory properties, but the cellular mechanisms by which they exert antiostcoarthritic and possibly antiinflammatory effects are still incompletely understood. The purpose of this study was to investigate the ability of diacerhein and them to inhibit the activation of the transcription factor nuclear factor-kappabeta, induced by the proinflammatory cytokine nterleukin-1beta, in primary monolayer cultures of bovine articular chondrocytes. We also studied the ability of diacerhein and them to prevent the expression of the inducible nitric oxide synthase gene, which is driven by nuclear factor-kappabeta. We observed that interleukin-1beta induced the degradation of the inhibitor kappabetaalpha protein and the translocation of the protein p65 (a member of the nuclear factor-kappabeta family) to the nucleus, which were inhibited by diacerhein and them, in a dose-dependent manner. Interleukin-1beta-induced nuclear factor-kappabeta binding to a specific (gamma-P-32)-labelled oligonucleotide probe was also inhibited by treatment of chondrocytes with diacerhein or rhein, as revealed by electrophoretic mobility shift assay. Inducible nitric oxide synthase mRNA and protein synthesis and nitric oxide production were also inhibited by diacerhein and them, in a dose-dependent manner. The half-maximal inhibitory concentrations of diacerhein and rhein, relative to nitric oxide production, were 8.2 muM and 7.7 muM, respectively. These results suggest that diacerhein and rhein inhibit nuclear factor-kappabeta activation and, consequently, the expression of nuclear factor-kappabeta-dependent genes, such as the inducible nitric oxide synthase gene, which can explain their antiosteoarthritic and antiinflammatory effects.