CD23, a low-affinity receptor for IgE, was recently shown to bind to CD11b and CD11c molecules on human monocytes. The 25-kDa soluble fragment of CD23 (sCD23), was tested for its capacity to elicit various signaling pathways in human monocytes. sCD23 was found to trigger an early increase in cGMP accumulation, through the generation of nitric oxide. This was a result of activating the L-arginine pathway, since the sCD23-mediated effect was inhibited in the presence of substituted nonmetabolizable L-arginine analogues. In addition, the increase in cGMP was suppressed by calcium chelators and inhibitors of the calcium/calmodulin complex, suggesting the involvement of a constitutive, calcium-dependent nitric oxide synthase (NOS). Indeed, the presence of an endothelial constitutive type III NOS mRNA was detected in nonactivated human monocytes, and the corresponding protein has been detected by flow cytometry. Moreover, sCD23 was shown to induce a calcium influx in monocytes, in accordance with an activation of a constitutive NOS through a transient increase in [Ca2+]i. As expected, these events were mimicked by mAbs against CD11b and CD11c, the macrophage receptors for CD23. In addition to these early events, sCD23 and the agonistic anti-CD11b and CD11c mAbs, which all trigger the release of proinflammatory mediators such as TNF-alpha, were shown to act through an NO-dependent process.