In vitro effects of diacerhein and rhein on interleukin 1 and tumor necrosis factor-alpha systems in human osteoarthritic synovium and chondrocytes

J Rheumatol. 1998 Apr;25(4):753-62.

Abstract

Objective: To evaluate the in vitro effects of diacerhein, a new drug for the treatment of osteoarthritis (OA), and its active metabolite, rhein, on interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) synthesis and expression in human OA synovial membrane, and on the IL-1beta and TNF-alpha receptors on human OA chondrocytes.

Methods: Levels of IL-1beta and TNF-alpha were determined using specific ELISA in culture medium of human synovial membrane explants incubated in the presence of 1 microg/ml of lipopolysaccharide with or without therapeutic concentrations of diacerhein (1.4, 2.7, 5.4 x 10(-5) M) and rhein (1.7, 3.5, 7.0 x 10(-5) M). IL-1beta mRNA level was quantitated by Northern blotting. Using radioligand binding experiments, we determined the effects of these agents on the density and affinity of chondrocyte IL-1 and TNF receptors.

Results: IL-1beta synthesis was significantly inhibited by diacerhein and rhein, with maximum inhibition at 5.4 x 10(-5) M for diacerhein (p < 0.02) and 3.5 x 10(-5) M for rhein (p < 0.05). The effect of both agents on IL-1beta was found to be translational and/or post-translational, judging by the absence of effect on gene expression level. Both agents produced dose and time dependent decreases in the number of IL-1 receptors (IL-1R) on OA chondrocytes. This effect was mediated through a reduction in the level of the type I IL-1R as shown by experiments using a blocking monoclonal antibody against this receptor type. Both agents also markedly reduced the IL-1 induced synthesis and expression of stromelysin 1. Neither diacerhein nor rhein significantly affected the level of synthesis of TNF-alpha or the level of TNF-R.

Conclusion: Diacerhein and rhein can effectively inhibit the synthesis of IL-1beta on human OA synovium, as well as the action of this cytokine at the cartilage level, by reducing the number of chondrocyte IL-1R. The effects of these agents seemed "selective" to the IL-1 system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anthraquinones / pharmacology*
  • Blotting, Northern
  • Cells, Cultured
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism*
  • Culture Techniques
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Interleukin-1 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Male
  • Matrix Metalloproteinase 3 / metabolism
  • Middle Aged
  • Osteoarthritis / metabolism*
  • Receptors, Interleukin-1 / metabolism
  • Receptors, Tumor Necrosis Factor / metabolism
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Anthraquinones
  • Enzyme Inhibitors
  • Interleukin-1
  • Lipopolysaccharides
  • Receptors, Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • diacerein
  • Matrix Metalloproteinase 3
  • rhein