Membrane expression and shedding of tumour necrosis factor receptors during activation of human blood monocytes: regulation by desferrioxamine.
Previous studies have shown that desferrioxamine (DFX), an iron chelator preventing the synthesis of hydroxyl radical (OH.), up-regulates the cell-surface expression of tumour necrosis factor-alpha (TNF-alpha) receptors on unactivated human blood monocytes. In the present study, we investigated the regulatory action of DFX on 125I-TNF-alpha binding to monocytes upon exposure to bacterial lipopolysaccharide (LPS). Exposure to LPS (1 microgram/ml) resulted in almost complete loss of 125I-TNF-alpha binding to the surface of monocytes. This down-regulation was reversible and the recovery observed after 18 hr was enhanced by addition of DFX (5 mM). However, binding studies on monocytes pre-exposed to low pH suggested that the DFX-induced increase of 125I-TNF-alpha binding was not due to differences in the number of receptors available but was probably due to a reduction of receptor occupancy by endogenously generated TNF-alpha. Time-course studies of TNF-alpha release from monocytes confirmed the ability of DFX to reduce the extracellular concentration of bioactive TNF-alpha through a decrease of its synthesis and an increase of its inactivation. The latter process was associated with an increased expression of the soluble form of TNF-alpha receptor type II. These results indicate that, in the presence of LPS, DFX increases the release of soluble TNF-alpha receptors from monocytes. Thus, conversely, OH. generated in situ could reduce the shedding of soluble TNF-alpha receptors and, hence, increase the widespread release of bioactive TNF-alpha.
Philippe
C
C
Institut National de la Santé et de la Recherche Médicale, Hôpital Tenon, Paris, France.
Roux-Lombard
P
P
Fouqueray
B
B
Perez
J
J
Dayer
J M
JM
Baud
L
L
D002462:Cell Membrane / Q000276:immunology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008070:Lipopolysaccharides / Q000276:immunology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003676:Deferoxamine