IGE SECRETION IS ATTENUATED BY AN INHIBITOR OF PROTEOLYTIC PROCESSINGOF CD23 (FC-EPSILON-RII)

CD23, the low-affinity IgE receptor, is up-regulated on interleukin (I L)-4-stimulated B cells and monocytes, with a concomitant increase in the release of soluble fragments of CD23 (sCD23) into the medium by pr oteolytic processing of the surface-bound intact CD23. The effect of i nhibition of the processing of CD23 on IgE production in human and mou se cells and in a mouse model in vivo was evaluated. CD23 processing t o sCD23 from RPMI 8866 (a human Epstein-Barr virus-transformed B cell line) cell membranes was inhibited by a broad-spectrum matrix-metallop rotease inhibitor, batimastat, with an IC50 of 0.15 mu M. Batimastat a lso inhibited CD23 processing in whole RPMI 8866 cells as well as in I L-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 in hibition of CD23 processing. Release of soluble fragments of CD23 in t he cell supernatants of tonsil B cells was inhibited over the concentr ation range of 1-10 mu M batimastat and intact cell surface CD23 was i ncreased on mouse splenic B cells in the presence of these concentrati ons of batimastat. IgE production of IL-4-stimulated human peripheral blood mononuclear cells was also blocked by 1-10 mu M batimastat, agai n with comparable inhibition of sCD23 release over the same concentrat ion range. Finally, in a mouse model of IgE production, batimastat inh ibited 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 therapeut ically relevant control point in the regulation of IgE synthesis.