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 b y an unknown metalloprotease. Two metalloprotease inhibitors, compound A (N -[4-hydoxyamino-2-(R)-isobutyl-3-(S)propargylthiomethylsuccinyl]-(S)-phenyl alnine-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 product ion. The ability of these inhibitors to block cleavage of murine CD23 and i mmunoglobulin production in an in vitro system was examined. The inhibitors blocked sCD23 release from B cells. The inhibitors also decreased IgE prod uction 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 o n immunoglobulin production did not require the presence of CD23 in that th ese 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 antibo dy-forming cells (AFC) while having no effect on cell proliferation or viab ility. The level of IF, transcripts in cells treated with compounds A and B were not different as compared with control cells. These results suggest t hat while these inhibitors effectively inhibit IgE production in a CD23-spe cific manner in the human, these compounds, in the mouse, inhibit immunoglo bulin production by an unknown mechanism that is unrelated to CD23.