Targeting pre-ligand assembly domain of TNFR1 ameliorates autoimmune diseases - an unrevealed role in downregulation of Th17 cells

J Autoimmun. 2011 Nov;37(3):160-70. doi: 10.1016/j.jaut.2011.05.013. Epub 2011 Jul 1.

Abstract

The pre-ligand assembly domain (PLAD) of tumor necrosis factor receptors mediates specific ligand-independent receptor assembly and subsequent signaling. However, the physiological role of PLAD in the regulation of TNFR-mediated immune responses in autoimmunity is still unclear. By using the recombinant PLAD.Fc protein to block TNFR1 assembly, we demonstrated that PLAD.Fc treatment significantly reduced the TNFR1-driving proinflammatory cytokines and protected NOD mice from diabetes. Strikingly, Th17 differentiation was significantly inhibited in PLAD.Fc-treated NOD and TNFR1-deficient mice, indicating a TNFR1-dependent Th17 development. PLAD.Fc-modulated effects on DCs, in terms of the downregulation of Th17-inducing cytokines, IL-6 and TGF-β, explained the potential mechanism for Th17 suppression. Finally, we provided an additional result that PLAD.Fc administration diminished the infiltration of Th17 cells in the central nervous system and ameliorated the experimental autoimmune encephalomyelitis in mice. Collectively, these data demonstrated that targeting PLAD of TNFR1 provides protection from autoimmune diseases through the downregulation of Th17 and suggested a therapeutic potential of PLAD-modulation in TNF-involved inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / drug effects*
  • Autoimmunity / genetics
  • Cell Differentiation
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Central Nervous System / drug effects
  • Central Nervous System / immunology
  • Central Nervous System / pathology
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Down-Regulation
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Female
  • Humans
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / immunology
  • Jurkat Cells
  • Mice
  • Mice, Inbred NOD
  • Molecular Targeted Therapy
  • Plasmids
  • Protein Structure, Tertiary
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology*
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Th17 Cells / drug effects*
  • Th17 Cells / immunology
  • Transfection
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / immunology

Substances

  • Interleukin-6
  • PLAD.Fc fusion protein
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • Transforming Growth Factor beta