UP-REGULATION OF TUMOR-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 I-125-TNF-alpha to its receptors. Scavengers of superoxide anion or hydrogen peroxide were without effect. DFX-induced up-regulation of I-125-TNF-alpha binding depended on the concentration of the drug (15 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.