Intravenous Immunoglobulin Modulates Human Mononuclear Phagocyte Tumor Necrosis Factor-α Production In Vitro

Abstract

CBMO, cord blood monocyte IFN-'Y, interferon-'Y TNF/cachectin constitutes one of the major inflammatory mediators secreted by activated monocytes and macrophages (I); it is implicated as a primary and proximal mediator ofendotoxic shock (2) and plays a physiologic role in inflammation. Receptors for the Fe domain of immunoglobulins are involved in the regulation of various monocyte/macrophage immune functions, including phagocytosis (3), antibody-dependent cell-mediated cytotoxicity (4), the clearance of immune complexes (5), and the secretion of inflammatory mediators (6). Among the secretory products induced by Fe interactions are leukotrienes (7), prostaglandins (8), various hydrolytic enzymes (9), and multiple cytokines, including IL-I (10), IL-6 (II), and TNF (12). Debets et al. (12) showed that when monocyte Fe receptors bound with cytophilic human IgG were cross-linked by the addition of antihuman IgG, rapid secretion of TNF was induced. These experiments were conducted with adherent adult human monocytes; soluble IgG alone failed to induce a response. In subsequent work, Debets et al. (13) demonstrated that cross-linking of FcR was not sufficient for the induction ofTNF but that high affinity Fc-FcR interactions are required. Kuhnert et al. (14) demonstrated the induction of TNF and

Differential regulation of myelin phagocytosis by macrophages/microglia, involvement of target myelin, Fc receptors and activation by intravenous immunoglobulins

“…Macrophages and microglia show very different responses to activation signals (Smith et al, 1998a) and there are clear differences in their ingestion rate of myelin (Mosley and Cuzner, 1996); both cell types, however, can be stimulated to phagocytose myelin by e.g., cytokines or antibody. Intravenous immunoglobulins (IVIg) represent an activating substance that is capable of activating different macrophage/microglia functions (Darville et al, 1994;Andersson et al, 1996;Aukrust et al, 1997).…”

Endocytosis of Uncleaved Tumor Necrosis Factor-α in Macrophages

“…Overproduction and secretion of TNF-␣ contributes to the acute symptoms of septic shock (Tracey, 1991), and to the more chronic effects of diseases such as rheumatoid arthritis and Crohn's disease (Beutler, 1999). The murine macrophage cell line RAW264 is widely used in studies of the regulation of TNF-␣ production (Darville et al, 1994;Kol et al, 1998). Exposure of RAW264 cells to bacterial lipopolysaccharide (LPS) leads to the rapid appearance of TNF-␣ mRNA (Chang et al, 1999) and a rapid accumulation of TNF-␣ protein in the Golgi complex (Shurety et al, 2000).…”

Human Antibodies to Bacterial Superantigens and Their Ability To Inhibit T-Cell Activation and Lethality

“…This is extremely important because variations in titers against BSAgs among different lots of IVIG have been reported (15). Fluctuations in titers may have altered the outcome of the experiments and make it very difficult to compare the different studies (7,8,21,23). Moreover, in previous studies the efficacy of IVIG preparations in vivo was not examined and in vivo protection studies were not performed.…”

“…These investigators suggested that inhibition of T-cell responses was due to specific suppression of binding or T-cell recognition of the BSAg. Other studies demonstrated that cytokine suppression was intimately linked to the ability of IVIG to neutralize the BSAgs (7,8,25). In one study, in vitro treatment of mononuclear cells with IVIG substantially inhibited the release of inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) induced by SEB (25).…”