Regulated expression and inhibitory function of FcγRIIb in human monocytic cells

Abstract

Human monocytes/macrophages express three classes of receptors for IgG: FcγRI, FcγRII, and FcγRIII. The expression and function of these receptors has been extensively studied with the exception of one, FcγRIIb. While the mRNA for FcγRIIb has been detected in human monocytes, the protein has remained elusive. Studies in mouse models indicated that the macrophage FcγRIIb serves to down-regulate FcγR-mediated phagocytosis and immune complex-induced inflammation. FcγRIIb has also been shown to modulate the action of cytotoxic antibodies against tumors in mouse models. Hence, an understanding of how FcγRIIb expression is regulated is of great importance. Here we demonstrate for the first time FcγRIIb protein expression and function in human monocytes. We also report that the expression of FcγRIIb is highly up-regulated by interleukin-4, a Th2 cytokine, and that the up-regulation of FcγRIIb results in a decrease in the phagocytic efficiency of interleukin-4-treated THP-1 cells. Furthermore co-clustering FcγRIIb with FcγRIIa resulted in enhanced phosphorylation of the inositol phosphatase SHIP, association of SHIP with Shc, and phosphorylation of additional proteins around 120 and 60-65 kDa, with a concomitant attenuation of Akt activation. We, therefore, propose that FcγRIIb serves to inhibit FcγRI/IIa-mediated macrophage activation using SHIP as its effector.