Fc gamma receptor cross-linking down-regulates IL-1 receptor antagonist and induces IL-1 beta in mononuclear phagocytes stimulated with endotoxin or Staphylococcus aureus.

Abstract

The cross-linking of monocyte Fc gamma R is a potent stimulus for IL-1ra production but does not induce IL-1 beta. However, during systemic infection, IgG-coated bacteria can activate mononuclear phagocytes via both cell wall components and opsonized IgG. Therefore, we analyzed the effect of combinations of Fc gamma R cross-linking and bacterial cell wall components on mononuclear phagocyte IL-1 beta and IL-1ra production. Human mononuclear cells and monocytes were cultured either alone or with combinations of immobilized IgG, LPS, or heat-killed Staphylococcus aureus (HKSA). Cells cultured on immobilized IgG released large amounts of IL-1ra but no detectable IL-1 beta. In response to LPS, mononuclear cells released IL-1ra at 1000-fold lower doses of LPS than was required to induce IL-1 beta. However, when measured in the presence of immobilized IgG, the LPS sensitivity for IL-1 beta release increased 100-fold, whereas IL-1ra release correlated inversely with the LPS dose. Furthermore, HKSA, a nonendotoxin stimulus, affected mononuclear cell IL-1 beta and IL-1ra release similarly. In addition, polymyxin B, a specific endotoxin inhibitor, blocked the LPS, but not the HKSA-induced changes in IL-1 beta and IL-1ra secretion, irrespective of immobilized IgG co-stimulation. In summary, these results suggest that mononuclear phagocyte stimulation with immobilized IgG favors IL-1ra over IL-1 beta production. Conversely, the addition of LPS or HKSA to the Fc gamma R-stimulated cells augments IL-1 beta but suppresses IL-1ra production.