INTRAVENOUS IMMUNOGLOBULIN MODULATES HUMAN MONONUCLEAR PHAGOCYTE TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION IN-VITRO

Mononuclear phagocytes (MO) secrete tumor necrosis factor-alpha (TNF) in response to inflammatory stimuli most notably the bacterial product lipopolysaccharide (LPS). Cross-linking of MO Fc receptors also induc es TNF release. Immunoglobulin for i.v. use is currently being investi gated for the treatment and prophylaxis of neonatal sepsis and for the treatment of various syndromes of autoimmune dysfunction in children and adults. We examined the in vitro effect of immunoglobulin-gamma (I gG) on neonatal (cord blood) monocyte and adult MO TNF production. Kin etic studies were performed on MO incubated with IgG alone and on MO p reincubated with IgG and stimulated with interferon-gamma/LPS. Incubat ion of MO in IgG (1-25 g/L) for 2, 6, and 24 h did not stimulate TNF s ecretion or production. However, enhanced TNF secretion was detected i n MO preincubated in IgG and subsequently stimulated with interferon-g amma/LPS. TNF secretion by cord blood monocytes was increasingly enhan ced by preincubation for 6 h with 1, 10, and 25 g/L IgG (2413.1 +/- 13 89.4, p < 0.05; 4070.4 +/- 3069.2, p < 0.005; and 6383.7 +/- 2982.2, p < 0.005 versus 1215 +/- 575.9 ng/L, respectively, in cells preincubat ed in medium alone). Significant enhancement was also detected in cord blood monocytes preincubated in IgG for 2 h. TNF secretion by adult M O was similarly enhanced (6082.0 +/- 1732.8, p < 0.05; 7158.8 +/- 3938 .2, p < 0.05; and 7302.7 +/- 3451.4, p < 0.05 versus 3353.2 +/- 2946.7 ng/L for 1, 10, and 25 g/L IgG, respectively, versus preincubation in medium alone). In additional experiments performed with Fc, Fab, and F(ab')(2) fragments, only F(ab')(2) fragments yielded positive results . Northern analyses revealed increased levels of mRNA for TNF only whe n 25 g/L IgG were used for preincubation. Preincubation in the lower c oncentrations of IgG did not result in increased accumulations of TNF mRNA. Thus, IgG acts primarily posttranscriptionally to enhance interf eron-gamma/LPS-induced TNP release in vitro.