Endotoxin triggers tumor necrosis factor (TNF)-dependent cytotoxicity from interferon-γ (IFN-γ) primed and unprimed human monocytes

Under endotoxin-free conditions, the authors have found that human peripheral blood mononuclear cells (PBM) lack spontaneous monocyte-mediated cytotoxicity against actinomycin D-treated WEHI 164 target cells in a 6 hr 51Cr release assay. However, small amounts of endotoxin (e.g., LPS) rapidly induce monocyte-mediated cytotoxicity. IFN-γ alone is incapable of inducing monocyte cytotoxicity. Instead, pretreatment of PBM with IFN-γ for 36 hr or more primes them for triggering by amounts of endotoxin that are almost 100-fold less than that required for unprimed cells. These conditions are analogous to the two step activation sequence described for mice where IFN-γ primes and LPS triggers macrophage cytotoxic capacity. Additionally, the authors have observed that neutralizing anti-TNF monoclonal antibody abolishes the cytotoxicity measured here; and rTNF is directly cytotoxic to the target cells used in this assay. Thus, TNF is both necessary and sufficient for the monocyte mediated cytotoxicity. Since IFN-γ is thought to be produced during a variety of immunological reactions, these findings may help to explain the augmented capacity of immunologically stimulated animals for LPS-triggered TNF production and their enhanced sensitivity to the lethal effects of endotoxin