Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors.
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.
Hawari
Feras I
FI
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Rouhani
Farshid N
FN
Cui
Xinle
X
Yu
Zu-Xi
ZX
Buckley
Caitriona
C
Kaler
Maryann
M
Levine
Stewart J
SJ
D015703:Antigens, CD / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D002384:Catalysis; D042783:Endothelial Cells / Q000737:chemistry; D004848:Epithelium / Q000737:chemistry; D006801:Humans; D008168:Lung / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry; D045726:Metalloproteases / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D045726:Metalloproteases