Fcγ-receptor signaling augments the LPS-stimulated increase in serum tumor necrosis factor-α levels

Abstract

The phagocytosis of IgG-coated erythrocytes (EIgG) has been shown to augment the bacterial lipopolysaccharide (LPS)-stimulated increase in serum tumor necrosis factor-α (TNF-α) levels. The present study evaluated the role of Fcγ-receptor (FcγR) signaling and complement activation in the effect of EIgG on the TNF-α response to LPS. The role of FcγR was determined using FcR γ-chain knockout mice that lack functional FcγRI and FcγRIII. In wild-type animals, EIgG caused a 16-fold augmentation of the serum TNF-α response to LPS, whereas there was no augmentation in the FcγR-deficient animals. Heat-damaged erythrocytes also augmented the TNF-α response to LPS. This effect was absent in FcγR-deficient animals. An IgG antibody against heated erythrocytes was detected in mouse serum. The complement activation caused by EIgG had little effect on the LPS-stimulated increase in serum TNF-α levels as indicated by activation of complement with cobra venom factor or IgM-coated erythrocytes as well as studies with C5-deficient mice. These results indicate that FcγR signaling primarily mediates the augmented serum TNF-α response to LPS caused by EIgG.