Regulation of Tumor Necrosis Factor Receptors on Phagocytes

Abstract

Tumor necrosis factor (TNF)-α is a cytokine secreted by monocytes, macrophages, T cells, natural killer cells, mast cells, and neutrophils (PMN) in response to stimulation in vitro with lipopolysaccharide (LPS), viruses, antigens, and during infection, allograft rejection or injury (1–4). Named for its ability to induce hemorrhagic necrosis of tumors (1), TNFα is also implicated as an important mediator of inflammation, septic shock, and cachexia (2). TNFβ or lymphotoxin is a lymphocyte-derived homolog of TNFα that shows many of the same properties (2). TNFα exerts its cytotoxic and immunologic activities by interacting with specific cell surface receptors (TNF-R) that it shares with TNFβ. The receptors exist on a variety of normal and malignant cells, reflecting a wide spectrum of targets for these two cytokines.

Modulation of TNF-R expression is an important means of regulating TNFα responses. Most TNF-R regulation studies were carried out with transformed cell lines. TNF-R on these cells are reported to be up-regulated by Type I and Type II interferons (5–10), interleukin 2 (11), and activators of protein kinase A (12), or down-regulated by interleukin 1 (13), activators of protein kinase C (12–16), cycloheximide (17), and both up- or down-regulated by the homologous ligand, TNFα (17–19).

Few studies address the regulation of TNF-R in primary phagocytes, even though macrophages and neutrophils are important targets for TNFα during inflammation. TNFα induces macrophage activation by itself or in combination with γ-interferon (IFNΓ). Macrophages respond to TNFα by demonstrating an increased ability to release toxic molecules, i.e., hydrogen peroxide (20–22) and nitric oxide (22), and to kill tumor cells (23, 24). TNFα is also a powerful PMN activator, promoting adherence to biological surfaces (25), stimulating phagocytosis (26, 27), respiratory burst activity (28), degranulation (27, 29), and antibody-dependent cytotoxicity (26).