Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation

Cytokine. 2012 Aug;59(2):252-7. doi: 10.1016/j.cyto.2012.04.012. Epub 2012 May 11.

Abstract

Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection.

MeSH terms

  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Monocytes / immunology
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / immunology
  • Osteogenesis / drug effects*
  • Tacrolimus / pharmacology*
  • Th17 Cells / cytology*
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-17
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Tacrolimus