Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-kappa(B). Implications for FK506 nephropathy

J Clin Invest. 1996 Jun 1;97(11):2433-9. doi: 10.1172/JCI118690.

Abstract

FK506 is a powerful immunosuppressive drug currently in use that inhibits the activation of several transcription factors (nuclear factor (NF)-AT and NF-kappaB) critical for T cell activation. We show here that, contrary to the situation in T cells, FK506 activates transcription factor NF-kappaB in nonlymphoid cells such as fibroblasts and renal mesangial cells. We further show that FK506 induces NF-kappaB-regulated IL-6 production in vitro and in vivo, in particular in kidney. IL-6 has been shown previously to produce renal abnormalities in vivo, such as mesangioproliferative glomerulonephritis. Similar renal abnormalities were also observed in FK506-treated animals. These results thus suggest a causal relationship between FK506-induced NF-kappaB activation/IL-6 production and some of FK506-induced renal abnormalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA-Binding Proteins / metabolism
  • Gene Expression / drug effects
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / immunology*
  • Glomerular Mesangium / pathology
  • Humans
  • I-kappa B Proteins*
  • Immunohistochemistry
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / toxicity
  • Interleukin-6 / analysis
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / urine
  • Kidney / drug effects
  • Kidney / immunology
  • Kidney / pathology*
  • L Cells
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Oligonucleotide Probes
  • Recombinant Fusion Proteins / biosynthesis
  • Tacrolimus / pharmacology*
  • Tacrolimus / toxicity

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Immunosuppressive Agents
  • Interleukin-6
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Oligonucleotide Probes
  • Recombinant Fusion Proteins
  • NF-KappaB Inhibitor alpha
  • Tacrolimus