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

Abstract

Hydroxy acid-based matrix metalloproteinase (MMP) inhibitors have been shown to inhibit tumor infiltration and growth, endotoxin shock, and acute graft-versus-host disease. Blockade of the release of soluble tumor necrosis factor-α (TNF-α) and CD95 ligand (CD95L; FasL) from cell-associated forms is reportedly involved in the mechanism of the drug effect. We investigated the effect of a MMP inhibitor, KB-R7785, on host resistance against Listeria monocytogenes infection, in which TNF-α is essentially required for the defense, in mice. The administration of KB-R7785 exacerbated listeriosis, while the drug prevented lethal shock induced by lipopolysaccharide and d-galactosamine. KB-R7785 inhibited soluble TNF-α production in spleen cell cultures stimulated by heat-killed L. monocytogenes and the drug treatment reduced serum TNF-α levels in infected mice, whereas the compound was ineffective on the modulation of interferon-γ and interleukin-10 production. The effect of KB-R7785 was considered to be dependent on TNF-α because the drug failed to affect L. monocytogenes infection in anti-TNF-α monoclonal antibody-treated mice and TNF-α knockout mice. Anti-CD95L monoclonal antibody was also ineffective on the infection. These results suggest that induction of infectious diseases, to which TNF-α is critical in host resistance, should be considered in MMP inhibitor-treated hosts.

Part of CIRS Nexus · Curated by Lauren Lowenstein, The Biotoxin Lady