Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection

Hydroxy acid-based matrix metalloproteinase (MMP) inhibitors have been show n to inhibit tumor infiltration and growth, endotoxin shock. and acute graf t-versus-host disease. Blockade of the release of soluble tumor necrosis fa ctor-alpha (TNF-alpha) and CD95 ligand (CD95L; FasL) from cell-associated f orms is reportedly involved in the mechanism of the drug effect. We investi gated the effect of a MMP inhibitor, KB-R7785, on host resistance against L isteria monocytogenes infection, in which TNF-alpha is essentially required for the defense, in mice. The administration of KB-R7785 exacerbated liste riosis, while the drug prevented lethal shock induced by lipopolysaccharide and D-galactosamine. KB-R7785 inhibited soluble TNF-alpha production in sp leen cell cultures stimulated by hear-killed L. monocytogenes and the drug treatment reduced serum TNF-alpha levels in infected mice, whereas the comp ound was ineffective on the modulation of interferon-gamma and interleukin- 10 production. The effect of KB-R7785 was considered to be dependent on TNF -alpha because the drug failed to affect L. monocytogenes infection in anti -TNF-alpha monoclonal antibody-treated mice and TNF-alpha. knockout mice. A nti-CD95L monoclonal antibody was also ineffective on the infection. These results suggest that induction of infectious diseases, to which TNF-alpha i s critical in host resistance, should be considered in MMP inhibitor-treate d hosts. (C) 2000 Federation of European Microbiological Societies. Publish ed by Elsevier Science B.V. Ail rights reserved.