Up-regulation of tumour necrosis factor-alpha receptors on monocytes by desferrioxamine.
The effect of endogenously generated reactive oxygen metabolites on the interaction of human blood monocytes with tumour necrosis factor-alpha (TNF-alpha) was investigated. Pre-exposure of unactivated human blood monocytes to dimethylthiourea, a scavenger of hydroxyl radical (OH.), or to desferrioxamine (DFX), an iron chelator preventing the synthesis of OH., enhanced the specific binding of 125I-TNF-alpha to its receptors. Scavengers of superoxide anion or hydrogen peroxide were without effect. DFX-induced up-regulation of 125I-TNF-alpha binding depended on the concentration of the drug (1-5 mM) and on the duration of the treatment (1-18 h). It was not due to a reduction of receptor occupancy by endogenously generated TNF-alpha. Scatchard analysis of binding data revealed that DFX caused an approximately two-fold increase in the number of type II TNF-alpha receptors, with no change in their affinity. This up-regulation, that did not require synthesis of new proteins, was associated with a decrease in the internalization rate of TNF-alpha receptors, the half-life of which was doubled. Conversely, these findings suggest that OH. generation by monocytes may have a physiological role in reducing the activity of membrane-associated TNF-alpha receptors.
Philippe
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 64, Hôpital Tenon, Paris, France.
Fouqueray
B
B
Perez
J
J
Baud
L
L
D001667:Binding, Competitive; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C038983:1,3-dimethylthiourea; D013890:Thiourea; D003676:Deferoxamine