IgE secretion is attenuated by an inhibitor of proteolytic processing of CD23 (FcεRII)

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Abstract
CD23, the low‐affinity IgE receptor, is up‐regulated on interleukin (IL)‐4‐stimulated B cells and monocytes, with a concomitant increase in the release of soluble fragments of CD23 (sCD23) into the medium by proteolytic processing of the surface‐bound intact CD23. The effect of inhibition of the processing of CD23 on IgE production in human and mouse cells and in a mouse model in vivo was evaluated. CD23 processing to sCD23 from RPMI 8866 (a human Epstein‐Barr virus‐transformed B cell line) cell membranes was inhibited by a broad‐spectrum matrix‐metalloprotease inhibitor, batimastat, with an IC50 of 0.15 μM. Batimastat also inhibited CD23 processing in whole RPMI 8866 cells as well as in IL‐4‐stimulated purified human monocytes with similar IC50. Batimastat inhibited IgE production from IL‐4/anti‐CD40‐stimulated human tonsil B cells as well as mouse splenic B cells in a manner consistent with inhibition of CD23 processing. Release of soluble fragments of CD23 in the cell supernatants of tonsil B cells was inhibited over the concentration range of 1–10 μM batimastat and intact cell surface CD23 was increased on mouse splenic B cells in the presence of these concentrations of batimastat. IgE production of IL‐4‐stimulated human peripheral blood mononuclear cells was also blocked by 1–10 μM batimastat, again with comparable inhibition of sCD23 release over the same concentration range. Finally, in a mouse model of IgE production, batimastat inhibited IgE production in response to ovalbumin challenge as determined by serum IgE levels. Taken together, the data support a role of CD23 in IgE production and point to CD23 processing to sCD23 as a therapeutically relevant control point in the regulation of IgE synthesis.