Regulated expression and inhibitory function of Fcgamma RIIb in human monocytic cells.
Human monocytes/macrophages express three classes of receptors for IgG: FcgammaRI, FcgammaRII, and FcgammaRIII. The expression and function of these receptors has been extensively studied with the exception of one, FcgammaRIIb. While the mRNA for FcgammaRIIb has been detected in human monocytes, the protein has remained elusive. Studies in mouse models indicated that the macrophage FcgammaRIIb serves to down-regulate FcgammaR-mediated phagocytosis and immune complex-induced inflammation. FcgammaRIIb has also been shown to modulate the action of cytotoxic antibodies against tumors in mouse models. Hence, an understanding of how FcgammaRIIb expression is regulated is of great importance. Here we demonstrate for the first time FcgammaRIIb protein expression and function in human monocytes. We also report that the expression of FcgammaRIIb is highly up-regulated by interleukin-4, a Th2 cytokine, and that the up-regulation of FcgammaRIIb results in a decrease in the phagocytic efficiency of interleukin-4-treated THP-1 cells. Furthermore co-clustering FcgammaRIIb with FcgammaRIIa 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 FcgammaRIIb serves to inhibit FcgammaRI/IIa-mediated macrophage activation using SHIP as its effector.
Tridandapani
Susheela
S
Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Siefker
Kristina
K
Teillaud
Jean-Luc
JL
Carter
Jo Ellen
JE
Wewers
Mark D
MD
Anderson
Clark L
CL
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D010587:Phagocytosis; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000737:chemistry* / Q000378:metabolism*; D012756:Sheep; D020298:U937 Cells; D015854:Up-Regulation
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017452:Receptors, IgG; D015847:Interleukin-4; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases