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Intravenous immunoglobulin modulates human mononuclear phagocyte tumor necrosis factor-alpha production in vitro
T Darville1, D Tabor, K Simpson
1Arkansas Children's Hospital, Little Rock 72202-3591.
Abstract:
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 induces TNF release. Immunoglobulin for i.v. use is currently being investigated 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 (IgG) on neonatal (cord blood) monocyte and adult MO TNF production. Kinetic studies were performed on MO incubated with IgG alone and on MO preincubated with IgG and stimulated with interferon-gamma/LPS. Incubation of MO in IgG (1-25 g/L) for 2, 6, and 24 h did not stimulate TNF secretion or production. However, enhanced TNF secretion was detected in MO preincubated in IgG and subsequently stimulated with interferon-gamma/LPS. TNF secretion by cord blood monocytes was increasingly enhanced by preincubation for 6 h with 1, 10, and 25 g/L IgG (2413.1 +/- 1389.4, 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 preincubated in medium alone). Significant enhancement was also detected in cord blood monocytes preincubated in IgG for 2 h. TNF secretion by adult MO 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Intravenous immunoglobulin (IgG) enhances tumor necrosis factor-alpha (TNF) production by monocytes when combined with inflammatory stimuli like LPS. This finding is relevant for treating neonatal sepsis and autoimmune diseases.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Mononuclear phagocytes (MO) produce tumor necrosis factor-alpha (TNF) in response to inflammatory stimuli, such as lipopolysaccharide (LPS).
- Intravenous immunoglobulin (IgG) is being explored for treating neonatal sepsis and autoimmune disorders.
- Fc receptor cross-linking on MO also triggers TNF release.
Purpose of the Study:
- To investigate the in vitro effect of immunoglobulin-gamma (IgG) on TNF production by neonatal and adult mononuclear phagocytes (MO).
- To determine if IgG alone or in combination with inflammatory stimuli influences TNF secretion.
Main Methods:
- Mononuclear phagocytes (neonatal cord blood and adult) were incubated with varying concentrations of IgG (1-25 g/L) for different durations (2, 6, 24 hours).
- Cells were either treated with IgG alone or preincubated with IgG followed by stimulation with interferon-gamma/lipopolysaccharide (LPS).
- TNF secretion was quantified, and experiments included Fc, Fab, and F(ab')2 fragments to identify the active component.
Main Results:
- IgG alone did not stimulate TNF secretion or production in MO.
- Preincubation with IgG significantly enhanced TNF secretion when MO were subsequently stimulated with interferon-gamma/LPS.
- This enhancement was observed in both neonatal and adult MO, with F(ab')2 fragments showing positive results, indicating the Fc region is not solely responsible.
Conclusions:
- Immunoglobulin-gamma (IgG) does not induce TNF production independently but potentiates inflammatory responses in mononuclear phagocytes (MO).
- The findings suggest a potential mechanism for IgG's therapeutic effects in inflammatory and infectious conditions.
- Further research into the interaction of IgG fragments with MO is warranted.