Multinucleated foreign body giant cells (FBGCs) form by monocyte-derived macrophage fusion on implanted biomedical devices and are believed to mediate oxidative damage to
biomaterial surfaces. Our in vitro system of human macrophage culture and
interleukin (IL)-4-induced FBGC formation was developed to study the macrophage fusion mechanism and the physiological significance of FBGCs on implanted
biomaterials and at other sites of chronic
inflammation. Here, we demonstrate that the
antioxidant vitamin E (90%
alpha-tocopherol) moderately induces macrophage fusion and increases IL-4-induced FBGC formation. Moreover, purified
alpha-tocopherol, but not beta-, gamma-, or
delta-tocopherol, most remarkably induces macrophage fusion, leading to cultures of confluent FBGCs below normal plasma concentrations. This is not observed with the similar
antioxidants probucol or
Trolox, suggesting that the
alpha-tocopherol effects on FBGC formation are independent of its
antioxidant activity. Consistent with the reported activation of
diacylglycerol kinase by
alpha-tocopherol, the
diacylglycerol kinase inhibitor
R59022 completely abrogates FBGC formation.
R59022 inhibition of IL-4-induced FBGC formation is reversed by
alpha-tocopherol, suggesting that FBGC formation involves
diacylglycerol kinase activation. This study suggests a novel role for
diacylglycerol kinase in the mechanism of macrophage fusion/FBGC formation at sites of chronic
inflammation and reveals that the pleiotropic lipophilic compound,
alpha-tocopherol, is a highly potent macrophage fusion factor.