Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluid

Abstract

Objectives. Lactoferrin is an iron-binding protein that is released from activated neutrophils at sites of inflammation and has anti-microbial as well as anti-inflammatory properties. This study set out to determine whether lactoferrin can delay neutrophil apoptosis and could act as a survival factor for neutrophils in SF.Methods. Human peripheral blood and SF neutrophils were incubated with iron-free lactoferrin and apoptosis determined after 9 h. SF from patients with RA was added to isolated neutrophils, with or without immunodepletion of lactoferrin, and effects on neutrophil apoptosis determined. Levels of lactoferrin in SF were assessed and related to disease duration and markers of disease activity.Results. Iron-free lactoferrin significantly delayed apoptosis of peripheral blood neutrophils, in a concentration-dependent manner after 9 h in culture (P < 0.04). Lactoferrin could also delay apoptosis of neutrophils isolated from SF of patients with RA. SF from patients with established RA delayed apoptosis of peripheral blood neutrophils and this effect was significantly reduced by depletion of lactoferrin (P < 0.03). Lactoferrin levels in SF from patients with established RA did not correlate with disease severity, but did correlate with markers of inflammation (CRP) and with the presence of RF. SF from patients with arthritis of <12 weeks duration did not contain significant levels of lactoferrin.Conclusion. Lactoferrin contributes to extended neutrophil survival in the rheumatoid joint in the established phase of RA but not in very early arthritis.

Aberrant Reactive Oxygen and Nitrogen Species Generation in Rheumatoid Arthritis (RA): Causes and Consequences for Immune Function, Cell Survival, and Therapeutic Intervention

“…Indeed, the synovial fluids from RA joints with significant synovial membrane hypertrophy are hypoxic and this environment lends itself to enhanced neutrophil survival (169). More recent data from Wong et al describes how neutrophil survival in the RA joint of patients with established disease may be mediated by increased concentrations of the iron binding protein, lactoferrin (304). The effects of lactoferrin on intracellular redox state remain unknown.…”

E2F1-directed activation of Bcl-2 is correlated with lactoferrin-induced apoptosis in Jurkat leukemia T lymphocytes

“…It is generally held that serum levels of Lf are predominantly neutrophilderived and in normal subjects usually remain below 10 lg/ml. However, under certain physiological conditions, cellular levels of Lf exposure can be considerably higher than this, and these higher Lf levels are strongly associated with a range of diseases (Wong et al 2009). In a previous study, a relatively high concentration of human Lf coupled with a natural iron saturation was shown to be sufficient to induce apoptosis in Jurkat leukemia T cells (Lee et al 2009b).…”

The Role of Neutr Ophils and Their Apoptosis in There Solution of Inflammation

“…Delayed apoptotic activity of peripheral blood neutrophils is observed in the course of various diseases, for example, respiratory distress syndrome in adults [25], sepsis [55][56][57][58], bacterial and viral pneumonia [59,60], exacerbation of bronchoectatic disease [61], rheumatoid arthritis [62], cystic fibrosis [63,64] and burns [65]. The correlation between the neutrophil apoptosis level and the disease severity is well established [55,58].…”