Soluble CD21 induces activation and differentiation of human monocytes through binding to membrane CD23

Interactions between CD23, the low-affinity receptor for IgE, and CD21,the C3d/EBV receptor, modulate several intracellular events in lymphocytes. A s oluble form of CD21 (sCD21) corresponding to the extracellular domain of th e receptor circulates in normal plasma. We now demonstrate that purified sC D21 acts as a functional ligand for CD23-expressing monocytes. Soluble CD21 induced an increase in intracellular cGMP levels and the production of IL- 6 and TNF-alpha in IL-4-pretreated monocytes induced to express CD23 but no t in unstimulated CD23(-) monocytes. The accumulation of cGMP and the produ ction of TNF-alpha were inhibited by N-G-monomethyl-L-arginine (L-NMMA), in dicating that sCD21 activates the L-arginine pathway of NO production. We d emonstrated that sCD21 activates NO synthase (NOS) since it was found to en hance the conversion of L-arginine into t-citrulline and induce the intrace llular expression of inducible NOS in CD23(+) monocytes. In addition, sCD21 was shown to up-regulate the expression of HLA-DR and CD40 and decrease th at of CD14 on cultured CD23(+) monocytes. Thus, in a fashion similar to IgE complexes, sCD21 is able to efficiently trigger CD23 signaling pathways, i nducing the release of pro-inflammatory mediators by human monocytes. Solub le CD21 up-regulates the expression of molecules involved in antigen presen tation, further suggesting a potential immunoregulatory function for the so luble molecule.