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Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling LAJAUNIAS, Frédéric, DAYER, Jean-Michel, CHIZZOLINI, Carlo Human CD33 is a myeloid-restricted transmembrane protein of the sialic acid-binding Ig-like lectin (Siglec) family. While structural analysis predicts an inhibitory function, it remains unknown under which circumstances CD33 may operate as an inhibitory molecule. Here we show that treatment of human monocytes with anti-CD33 mAb induces the production of the proinflammatory cytokines IL-1 beta, TNF-alpha, and IL-8. However, decreased CD33 surface expression obtained by RNA interference using cognate small interfering RNA (siRNA) was specifically paralleled by spontaneous cytokine production. Similarly, sialic acid (CD33 ligand) removal from the monocyte surface by neuraminidase resulted in IL-1 beta up-regulation, while the addition of red blood cells or sialyllactosamine (but not lactosamine) reversed the effect of neuraminidase treatment, thus demonstrating the importance of ligand recognition by CD33 for repression of monocyte activation. Finally, inhibition of phosphoinositide 3-kinase (PI3K) dramatically enhanced the IL-1 beta response to anti-CD33 and neuraminidase, while inhibition of p38 mitogen-activated protein [...] LAJAUNIAS, Frédéric, DAYER, Jean-Michel, CHIZZOLINI, Carlo. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. European Journal of Immunology, 2005, vol. 35, no. 1, p. 243-5