Metalloprotease inhibitor-mediated inhibition of mouse immunoglobulin production.

High levels of membrane CD23 have been shown to decrease immunoglobulin E (IgE). CD23 is a very labile molecule and is cleaved from the cell surface by an unknown metalloprotease. Two metalloprotease inhibitors, compound A (N-[4-hydoxyamino-2-(R)-isobutyl-3-(S)propargylthiomethylsuccinyl]-(S)-phenylalnine-N'-methyl-amide) and compound B (N-[3-(S)-hydroxy-4-hydroxyamino-2-(R)-(2-naphthylmethyl) succinyl]-(S)-tert-leucinamide), were chosen for their ability to inhibit human CD23 cleavage and selectively inhibit IgE production. The ability of these inhibitors to block cleavage of murine CD23 and immunoglobulin production in an in vitro system was examined. The inhibitors blocked sCD23 release from B cells. The inhibitors also decreased IgE production by B cells; however, 20-30 times more inhibitor was needed to give a similar amount of inhibition as compared with sCD23 release. The effects on immunoglobulin production did not require the presence of CD23 in that these inhibitors also blocked in vitro immunoglobulin production when B cells from CD23-/- mice were used. The inhibitors decreased production of all other immunoglobulin isotypes examined and reduced the number of IgE antibody-forming cells (AFC) while having no effect on cell proliferation or viability. The level of Iepsilon transcripts in cells treated with compounds A and B were not different as compared with control cells. These results suggest that while these inhibitors effectively inhibit IgE production in a CD23-specific manner in the human, these compounds, in the mouse, inhibit immunoglobulin production by an unknown mechanism that is unrelated to CD23.