Low affinity immunoglobulin gamma Fc region receptor III-A
macrophage activation
Induction of tumor necrosis factor alpha production by adhered human monocytes: a key role for Fcgamma receptor type IIIa in rheumatoid arthritis.
<h4>Objective</h4>Small IgG rheumatoid factor immune complexes may provide the trigger for macrophage-derived tumor necrosis factor alpha (TNFalpha) production in rheumatoid arthritis. Immune complexes may bind to any of 3 IgG Fc receptors (FcgammaR). Therefore, the ability of monocyte-derived macrophages to produce TNFalpha was examined following ligation of each of the 3 human FcgammaR, using murine monoclonal antibodies (mAb) to each receptor as a model for small immune complexes.<h4>Methods</h4>Adhered human monocytes expressing all 3 FcgammaR were incubated with murine anti-FcgammaR mAb directed against FcgammaRI, FcgammaRII, or FcgammaRIII. Supernatants were collected at various time points and tested for the presence of TNFalpha and interleukin-1alpha (IL-1alpha) by enzyme-linked immunosorbent assay.<h4>Results</h4>The anti-FcgammaRIII mAb induced adhered human monocytes to release TNFalpha. However, F(ab)2 and Fab fragments of the anti-FcgammaRIII mAb failed to induce TNFalpha production. TNFalpha was undetectable following incubation with the anti-FcgammaRI or anti-FcgammaRII mAb. Furthermore, blocking FcgammaRI or FcgammaRII had no effect on the levels of TNFalpha released in response to the anti-FcgammaRIII mAb. Of the 3 anti-FcgammaR mAb, only anti-FcgammaRIII induced IL-1alpha production from adhered human monocytes, and this was inhibited by the presence of a neutralizing anti-TNFalpha mAb.<h4>Conclusion</h4>This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain. In addition, IL-1alpha production following FcgammaRIIIA ligation appears to be dependent on the presence of TNFalpha.