C5a modulation of interleukin-1 beta-induced interleukin-6 production by human osteoblast-like cells

Periodontal bone resorption is controlled by osteoblast products, including interleukin (IL)-6, which are stimulated by other cytokines and complement components in the pro-inflammatory milieu. This study demonstrated that hu man osteoblast-like osteosarcoma cells (MG-63) responded to human recombina nt (hr) C5a by releasing significant amounts of the bone-resorbing cytokine IL-6. C5a-induced release of IL-6 was enhanced 330% when cells were expose d to IL-1 beta prior to C5a challenge at optimal concentrations (1.0 mu g/m l C5a, 0.1 ng/ml IL-1 beta). Cells simultaneously challenged with these con centrations of C5a and IL-1 beta produced a 700% increase in IL-6 release r elative to cells challenged with IL-1 beta alone. Incubation of IL-1 beta-t reated cells with anti-human C5a receptor (C5aR) Ab resulted in a 78% suppr ession of the C5a-induced release of IL-6, but C5aR neutralization did not affect C5a/IL-1 beta co-stimulation of IL-6. In addition, neither IL-1 beta nor C5a significantly altered the other's cell-surface receptor relative t o binding affinity or density. These results indicate that while MG-63 cell s express functional C5aRs, the synergistic effect of C5a and IL-1 beta on osteoblast IL-6 production is probably controlled by post-receptor signalin g events. C5a agonists and antagonist used to alter critical C5a concentrat ions may present a new point of therapeutic intervention for the treatment of inflammatory bone resorption such as is found in periodontitis.