Three TNFR-binding domains of PGRN act independently in inhibition of TNF-alpha binding and activity

Front Biosci (Landmark Ed). 2014 Jun 1;19:1176-85. doi: 10.2741/4274.

Abstract

PGRN was previously reported to bind to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we present further evidences demonstrating the PGRN inhibition of TNF-alpha binding and activity, and clarifying the distinct mechanisms underlying TNF-alpha inhibition between PGRN and classic TNF-alpha-binding inhibitors. In addition, we present evidences indicating that three TNFR binding domains of PGRN act independently in binding to TNFR. Furthermore, changing the order of three TNFR-binding domains in Atsttrin, a PGRN-derived molecule composed of these TNFR-binding domains, does not affect its anti-inflammatory and anti-TNF activities in both collagen-induced inflammatory arthritis and human TNF-alpha transgenic mouse model. Taken together, these findings provide the additional molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various inflammatory diseases and conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / prevention & control
  • Binding Sites / genetics
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Gene Expression / drug effects
  • HEK293 Cells
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Progranulins
  • Protein Binding / drug effects
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Two-Hybrid System Techniques
  • Vascular Cell Adhesion Molecule-1 / genetics

Substances

  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1