title: 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-alpha (TNF-alpha) 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-alpha 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-alpha production in spleen cell cultures stimulated by heat-killed L. monocytogenes and the drug treatment reduced serum TNF-alpha levels in infected mice, whereas the compound 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. Anti-CD95L monoclonal antibody was also ineffective on the infection. These results suggest that induction of infectious diseases, to which TNF-alpha is critical in host resistance, should be considered in MMP inhibitor-treated hosts.
authors.affiliation: Department of Bacteriology, Hirosaki University School of Medicine, Zaifu-cho 5, Hirosaki, Aomori 036-8562, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Yoshino
authors.forename: K
authors.initials: K
authors.lastname: Sekikawa
authors.forename: H
authors.initials: H
authors.lastname: Madarame
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: A
authors.initials: A
authors.lastname: Nakane
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015169:Colony Count, Microbial; D053222:Fas Ligand Protein; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007113:Immunity, Innate; D008070:Lipopolysaccharides; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology*; D012772:Shock, Septic / Q000401:mortality / Q000517:prevention & control; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006877:Hydroxamic Acids; C107086:KB R7785; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005998:Glycine