Tetanus toxin inhibits secretion of lysosomal contents from human macrophages

The mechanism by which tetanus toxin (TT) inhibits the release of neurotransmitters from neurons is unknown. Since secretion of lysosomal contents from monocytes/macrophages (MOs) appears to be similar to the release of synaptosomal contents from neural cells, we examined the effects of TT on MO secretion. Adherent human MOs were cultured overnight with or without TT (1.25 micrograms/ml), washed, and resuspended in TT-free medium. In response to the calcium ionophore A23187, TT-treated MOs secreted significantly less lysozyme (27.2% +/- 3.2%) than did control cells (48.6% +/- 6.8%; 44.1% inhibition, P less than .001). TT inhibition of A23187-stimulated release of lysozyme from MOs was dose dependent, and higher concentrations of A23187 could not overcome the inhibitory effect of TT. MO secretions in response to a second secretagogue, phorbol myristate acetate, was also inhibited by TT. Heated TT (100 C for 1 hr), which has no in vivo toxicity, also failed to inhibit MO secretion. The inhibition of secretion by TT required holotoxin. C- and B-fragments produced no appreciable effect on secretion in response to either secretagogue. These studies indicate that human MOs may be a readily accessible, model system for the study of the biochemical basis of TT intoxication. However, observations in this system must be confirmed in neurons, the natural site of TT intoxication.