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 the up-regulation of immunoglobulin E (IgE) synthesis. Production of sCD23 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 this enzyme may be a zinc-dependent metalloproteinase. Therefore, we investigated the effect of a standard hydroxamate-type Zn2+ metalloproteinase inhibitor (GI 129471) on both sCD23 and IgE release from human tonsillar B cells, stimulated with interleukin-4 (IL-4) and anti-CD40. Incubation 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 activity of the compound against sCD23 had decreased by greater than threefold (IC50 2+/-0.26 microM; n=3). On the other hand, GI 129471 caused a potent inhibition of IgE production, with no apparent loss of activity over the culture period (14 days: IC50 250 nm+/-72 nm; n=3). Time-course studies showed that, despite loss of activity against sCD23, 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, as no effect was seen on immunoglobulin G1 (IgG1) or IgG4 production at test concentrations as high as 10 microM. These results support the hypothesis that metalloproteinases may be involved in the proteolytic cleavage of CD23 and subsequent regulation of IgE synthesis. Inhibition of the protease(s) responsible for such cleavage may be of value in the treatment of allergic disease.
Department of Cell Biology, Rhône-Poulenc-Rorer Ltd, Dagenham Research Centre, Dagenham, Essex, UK.
D J
DJ
Wheeler
S
S
Parveen
K
K
Pollock
R J
RJ
Williams
D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D015847:Interleukin-4 / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D014066:Palatine Tonsil / Q000276:immunology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D017455:Receptors, IgE; D013997:Time Factors
D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D011480:Protease Inhibitors; D017455:Receptors, IgE; C088672:GI 129471; D015847:Interleukin-4; D007073:Immunoglobulin E; D010649:Phenylalanine; D008666:Metalloendopeptidases