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.

Increased Production of Matrix Metalloproteinases in Helicobacter pylori‐Associated Human Gastritis

“…MMP secretion has been more extensively studied in other bacterial infections and it is known that Mycobacterium tuberculosis is able to induce both MMP‐2 and MMP‐9 from murine macrophages [10]. Other infections capable of inducing MMPs include Lyme disease [27], chlamydial infections [28] and Listeria monocytogenes infection [11]. Bacterial products, such as mycobacterial cell walls, lipopolyaccharide and heat‐shock proteins [28–30], have also been shown to increase MMP secretion.…”

“…Recent evidence suggests that MMPs are major effector molecules causing tissue damage in ulcerative colitis [6]. Other studies have suggested that MMPs contribute to tissue remodelling processes, and possibly tissue damage, in bacterial infections [10,11]. MMPs can be induced both by bacterial products (e.g.…”

Infections in myelodysplastic syndromes

“…[40][41][42] MDS patients also have deficiencies in the contents of neutrophil granules, including quantitative and/or functional anomalies of myeloperoxidase, lactoferrin and antibiotic proteases such as elastase and cathepsin G, [43][44][45][46] deficiencies in granule membrane glycoproteins, 44 and matrix metalloproteinase dysfunction. [47][48][49] Impaired activity of granule proteases in neutrophils, which can induce tissue injury through an inflammatory-mediated process, is potentially implicated in the increased susceptibility to infections even in the absence of neutropenia. [50][51][52] However, these defects have still not been well defined in clinical studies.…”

Evaluation of MMP-9 and iNOS expressions in sheep with encephalitic listeriosis

“…Matrix metalloproteinases (MMPs) degrade all extracellular matrix (ECM) components and perform important tasks such as tissue remodeling and modulation of the immune system (39,45). Increased expression of MMPs is known in many central nervous system diseases such as multiple sclerosis, experimental autoimmune encephalomyelitis, alzheimer's disease, stroke and meningitis (38,42).…”