INHIBITION OF SCD23 AND IMMUNOGLOBULIN-E RELEASE FROM HUMAN B-CELLS BY A METALLOPROTEINASE INHIBITOR, GI-129471

Soluble CD23 (sCD23) has been proposed to play an important role in th e up-regulation of immunoglobulin E (IgE) synthesis. Production of sCD 23 is dependent on the proteolytic cleavage of membrane CD23, but the protease(s) involved in this process remain unknown. Preliminary data, obtained by testing a panel of protease inhibitors, suggested that th is enzyme may be a zinc-dependent metalloproteinase. Therefore, we inv estigated the effect of a standard hydroxamate-type Zn2+ metalloprotei nase inhibitor (GI 129471) on both sCD23 and IgE release from human to nsillar B cells, stimulated with interleukin-4 (IL-4) and anti-CD40. I ncubation of cells for 3 days with GI 129471 inhibited the production of sCD23 with an IC50 of 602 nM +/- 3 nM (n = 3), but by 14 days the a ctivity of the compound against sCD23 bad decreased by greater than th reefold (IC50 2 +/- 0.26 mu M; n = 3). On the other hand, GI 129471 ca used a potent inhibition of IgE production, with no apparent loss of a ctivity over the culture period (14 days: IC50 250 nM +/- 72 nM; n = 3 ). Time-course studies showed that, despite loss of activity against s CD23, inhibition of sCD23 production early in the culture was able to cause a potent and long-lasting inhibitory effect on IgE. Furthermore, we also showed that the activity of GI 129471 is selective for IgE, a s no effect was seen on immunoglobulin G1 (IgG1) or IgG4 production at test concentrations as high as 10 mu M. These results support the hyp othesis that metalloproteinases may be involved in the proteolytic cle avage of CD23 and subsequent regulation of IgE synthesis. Inhibition o f the protease(s) responsible for such cleavage may be of value in the treatment of allergic disease.