Engagement of Fc gamma receptors on leukocytes by immune complexes induces both cytokine production and immune complex internalization. The relationship between these processes is unclear. In many disease states, Fc gamma receptors encounter their ligands in deposited forms that cannot be readily internalized. In this study, we examined the kinetics of ERK1/2 phosphorylation and TNF-alpha secretion in primary human monocytes in response to soluble heat-aggregated IgG or surface-bound IgG, to mimic soluble immune complexes and tissue-deposited IgG, respectively. Soluble aggregated IgG induced transient signaling, leading to peak phosphorylation of ERK1/2 by 15 min and peak TNF-alpha levels by 1 h, whereas surface-bound IgG caused sustained responses over the course of several hours. Treatment with the vacuolar ATPase inhibitor bafilomycin led to increased persistence of ERK1/2 phosphorylation in response to aggregated IgG. When monocytes were incubated with both soluble aggregated IgG and surface-bound IgG simultaneously, ERK1/2 phosphorylation was transient. These results suggest that Fc gamma receptor internalization is an important step in termination of inflammatory signaling, and that small immune complexes can exert an overall down-modulatory effect when encountered in the presence of immobilized IgG. (C) 2010 Elsevier Inc. All rights reserved.