Intravenous immunoglobulin preparations promote apoptosis in lipopolysaccharide‐stimulated neutrophils via an oxygen‐dependent pathway in vitro

Abstract

Since prolonged survival of activated neutrophils has an autotoxic potential, neutrophil apoptosis plays an important role in the rapid resolution of inflammation. Intravenous immunoglobulin (IVIG) preparations, which are beneficial therapeutic agents for the treatment of autoimmune diseases and systemic inflammatory diseases, have been reported to induce apoptosis of lymphocytes and endothelial cells in vitro. In the present study, we investigated whether IVIG may induce apoptosis of neutrophils cultured in vitro. After neutrophils prestimulated with or without lipopolysaccharide (LPS) were cultured in the presence or absence of IVIG, the number of apoptotic cells, intracellular H2O2 and GSH were measured by a flow cytometer. IVIG induced apoptosis of LPS-stimulated neutrophils dose dependently, but not in unstimulated neutrophils. Although anti-Fas monoclonal antibodies (mAbs) had no effect on the IVIG-induced apoptosis in the LPS-stimulated neutrophils, anti-Fc gamma receptor (Fc gammaR) II- and III-blocking mAbs significantly inhibited the IVIG-induced apoptosis. IVIG increased the production of intracellular H2O2, while it decreased the production of GSH, in the LPS-stimulated neutrophils. Furthermore, a specific NADPH oxidase inhibitor and anti-oxidants inhibited the IVIG-induced neutrophil apoptosis. Therefore, these findings indicate that IVIG preparations induce apoptosis of LPS-stimulated neutrophils and suggest that the IVIG-induced apoptosis may be mediated by an oxygen-dependent pathway via Fc gammaRII and III.

Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies

“…However, this reduction was not equally distributed among the three monocytes subsets in that the decrease involved mainly the intermediate monocytes. The effect of IVIg on cells of the innate immunity has been analyzed in in vitro models, providing conflicting results [31][32][33]. Conflicting results were also observed on TNF-α levels before and after IVIg [34].…”

Intravenous Immunoglobulin-Induced Neutrophil Apoptosis in the Lung during Murine Endotoxemia

“…Hagiwara et al reported that administration of high-dose (1,000 mg/kg) IVIg reduced mortality and improved pulmonary pathology in a rat sepsis model via reduction of high mobility group box protein 1 (HMGB1) [8]. Takeshita et al reported that IVIg induced LPS-stimulated neutrophil apoptosis in vitro [9]. Thus, clinical/experimental studies reveal that IVIg may be a useful adjuvant anti-inflammatory treatment during sepsis, as it modulates inflammation.…”

The Role of Neutrophil Activation in the Pathogenesis of Kawasaki Disease

“…We previously reported that the apoptosis of neutrophils is inhibited during the acute phase of KD, and that an increase in the number of peripheral neutrophils may be associated with the delayed apoptosis of neutrophils [33]. Furthermore, IVIG can promote apoptosis in activated neutrophils in vitro by an oxygen-dependent pathway via FcγRII and III [34]. Actually, in KD patients, IVIG therapy is reported to decrease the number of circulating neutrophils by accelerating their apoptosis [35].…”