The control of mycobacterial
infections depends on the
cytokine-mediated activation of mononuclear phagocytes to inhibit the growth of intracellular mycobacteria. Optimal activation requires the presence of T-cell-derived
gamma interferon (IFN-gamma) and other signals, including
tumor necrosis factor (TNF). Recently, an 11-mer
peptide based on
amino acids 70 to 80 of the human TNF sequence,
TNF(70-80), was found to have TNF mimetic properties, which include the activation of human and mouse neutrophils to kill Plasmodia spp. Therefore, we investigated the capacity of
TNF(70-80) to activate the murine macrophage cell line RAW264.7 infected with the
vaccine strain Mycobacterium bovis bacillus Calmette-Guérin (BCG). When RAW264.7 cells were pretreated with human TNF or
TNF(70-80) in the presence of IFN-gamma, there was a dose-dependent reduction in the replication of BCG as measured by the uptake of 3H-labeled
uracil and a concomitant release of
nitric oxide as measured by the
nitrite in the culture supernatants. TNF- or TNF(70-80)-induced macrophage activation was dependent on IFN-gamma and was inhibited by neutralizing
monoclonal antibody to human TNF and by anti-IFN-gamma
antisera. Both
nitrite release and BCG growth inhibition were abrogated by competitive inhibitors of
L-arginine, which blocked the activation of
inducible nitric oxide synthase. A soluble form of the Type 1
TNF receptor blocked the activation of BCG-infected macrophages by human TNF and
TNF(70-80), demonstrating that the effect of
TNF(70-80) is dependent on signaling through
TNF receptor I. The mimetic effects of
TNF(70-80) on macrophage activation in vitro suggest that treatment with
TNF(70-80) may modulate mycobacterial
infections in vivo.