Complement plays a critical role in the detoxification of immune complexes by regulating their size and facilitating their removal. We demonstrate another consequence of complement opsonization: the regulation of the pro-inflammatory activities of leukocytes. Immune complexes were formed in the presence (opsonized complexes) or absence (unopsonized complexes) of normal human serum and purified on Protein A agarose. Complexes were incubated at 25-100 μg/ml with monocytic U937 cells or peripheral blood mononuclear cells (PBMC's). Cell supernates were examined for the presence of IL-1β, IL-6, IL-8, and GM-CSF. Immune complexes were also incubated with freshly-prepared human neutrophils and NADH/NADPH metabolic oscillations and superoxide production measured.

Complement significantly reduced the capacity of immune complexes to induce cytokine secretion from both PBMC's and U937 cells at concentrations above 25μg/ml. For each cytokine measured, opsonized immune complexes were 30-75% less efficient in inducing the cytokines of interest that unopsonized immune complexes. These results were statistically-significant for IL-1β, IL-6, and GM-CSF (p ≤ 0.05). Norhern blotting for IL-1β and IL-8 mRNA's showed that this effect was accompanied by decreased mRNA transcription of each cytokine. In human neutrophils, unopsonized immune complexes increased NAD(P)H metabolic oscillations from the 20-22 sec period normally seen in the resting state to the 10-12 sec period associated with neutrophil activation. Predictably, the increase in metabolic oscillation rate was associated with increases in superoxide production. Opsonized immune complexes increased neither the rate of metabolic oscillation nor superoxide production.

We conclude that complement opsonization significantly reduces the phlogistic potential of model immune complexes. These data support the concept of the biological heterogeneity of immune complexes and underline the importance of identifying the specific complexes which may have pro-inflammatory activity in diseases such as juvenile rheumatoid arthritis and systemic lupus.