Fc[Gamma]-receptor signaling augments the LPS-stimulated increase in serum tumor necrosis factor-[Alpha] levels

Refici, Marion L., Dennis W. Metzger, Bernard P. Arulanandam, Michelle R. Lennartz, and Daniel J. Loegering. Fc[Gamma]-receptor signaling augments the LPS-stimulated increase in serum tumor necrosis factor-[Alpha] levels. Am J Physiol Regulatory Integrative Comp Physiol 280: R1037-R1044, 2001.--The phagocytosis of IgG-coated erythrocytes (EIgG) has been shown to augment the bacterial lipopolysaccharide (LPS)-stimulated increase in serum tumor necrosis factor-[Alpha] (TNF-[Alpha]) levels. The present study evaluated the role of Fc[Gamma]-receptor (Fc[Gamma]R) signaling and complement activation in the effect of EIgG on the TNF-[Alpha] response to LPS. The role of Fc[Gamma]R was determined using FcR [Gamma]-chain knockout mice that lack functional Fc[Gamma]RI and Fc[Gamma]RIII. In wild-type animals, EIgG caused a 16-fold augmentation of the serum TNF-[Alpha] response to LPS, whereas there was no augmentation in the Fc[Gamma]R-deficient animals. Heat-damaged erythrocytes also augmented the TNF-[Alpha] response to LPS. This effect was absent in Fc[Gamma]R-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-[Alpha] 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 Fc[Gamma]R signaling primarily mediates the augmented serum TNF-[Alpha] response to LPS caused by EIgG. Fc receptor [Gamma]-chain knockout mice; sepsis; heat-damaged erythrocytes; complement activation; C5 knockout mice; cobra venom factor