Induction of tumor necrosis factor α production by adhered human monocytes: A key role for Fcγ receptor type IIIA in rheumatoid arthritis

Open Access
Publisher Website
Google Scholar
Abstract
Objective Small IgG rheumatoid factor immune complexes may provide the trigger for macrophage-derived tumor necrosis factor α (TNFα) production in rheumatoid arthritis. Immune complexes may bind to any of 3 IgG Fc receptors (FcγR). Therefore, the ability of monocyte-derived macrophages to produce TNFα was examined following ligation of each of the 3 human FcγR, using murine monoclonal antibodies (mAb) to each receptor as a model for small immune complexes. Methods Adhered human monocytes expressing all 3 FcγR were incubated with murine anti-FcγR mAb directed against FcγRI, FcγRII, or FcγRIII. Supernatants were collected at various time points and tested for the presence of TNFα and interleukin-1α (IL-1α) by enzyme-linked immunosorbent assay. Results The anti-FcγRIII mAb induced adhered human monocytes to release TNFα. However, F(ab)2 and Fab fragments of the anti-FcγRIII mAb failed to induce TNFα production. TNFα was undetectable following incubation with the anti-FcγRI or anti-FcγRII mAb. Furthermore, blocking FcγRI or FcγRII had no effect on the levels of TNFα released in response to the anti-FcγRIII mAb. Of the 3 anti-FcγR mAb, only anti-FcγRIII induced IL-1α production from adhered human monocytes, and this was inhibited by the presence of a neutralizing anti-TNFα mAb. Conclusion This study suggests a dominant role for FcγRIIIA in the induction of both TNFα and IL-1α production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFα production may require the ligation of either 3 FcγRIIIA receptors or only 2 FcγRIIIA receptors, where one interaction must involve binding via an Fc domain. In addition, IL-1α production following FcγRIIIA ligation appears to be dependent on the presence of TNFα.

This publication has 0 references indexed in Scilit: