Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors

Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1297-302. doi: 10.1073/pnas.0307981100. Epub 2004 Jan 26.

Abstract

Soluble tumor necrosis factor receptors (TNFRs) are important modulators of TNF bioactivity. Proteolytic cleavage of the 28-kDa ectodomain of TNFR1 has been recognized as the mechanism by which soluble TNFR is shed. We now describe the release of exosome-like vesicles as a mechanism for the generation of soluble, full-length 55-kDa TNFR1. We found unexpectedly that the predominant form of soluble TNFR1 in human serum and lung epithelial lining fluid is a full-length 55-kDa protein. Furthermore, supernatants from human vascular endothelial cells contain only full-length 55-kDa TNFR1 that can be sedimented by high-speed centrifugation, floated on sucrose gradients at a density of 1.1 g/ml, and associated with vesicles that range in diameter from 20 nm to 50 nm. We conclude that the release of TNFR1 exosome-like vesicles represents a previously unrecognized mechanism by which constitutive production of soluble cytokine receptors may be regulated, independent of ectodomain cleavage by receptor sheddases.

MeSH terms

  • Antigens, CD / analysis
  • Antigens, CD / blood
  • Antigens, CD / metabolism*
  • Catalysis
  • Endothelial Cells / chemistry
  • Epithelium / chemistry
  • Humans
  • Lung / chemistry
  • Membrane Microdomains / chemistry
  • Metalloproteases / physiology
  • Receptors, Tumor Necrosis Factor / analysis
  • Receptors, Tumor Necrosis Factor / blood
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, CD
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Metalloproteases