Yamada K, Yoshino K, Sekikawa K, Madarame H, Yagita H, Nakane A
Department of Bacteriology, Hirosaki University School of Medicine, Zaifu-cho 5, Hirosaki, Aomori 036-8562, Japan.
FEMS Immunol Med Microbiol. 2000 Nov;29(3):187-94. doi: 10.1111/j.1574-695X.2000.tb01522.x.
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.
基于羟基酸的基质金属蛋白酶（MMP）抑制剂已被证明可抑制肿瘤浸润和生长、内毒素休克及急性移植物抗宿主病。据报道，阻断可溶性肿瘤坏死因子-α（TNF-α）和CD95配体（CD95L；FasL）从细胞相关形式的释放参与了药物作用机制。我们研究了MMP抑制剂KB-R7785对小鼠抵抗单核细胞增生李斯特菌感染的宿主抵抗力的影响，其中TNF-α对防御至关重要。给予KB-R7785会加重李斯特菌病，而该药物可预防脂多糖和D-半乳糖胺诱导的致死性休克。KB-R7785抑制了热灭活的单核细胞增生李斯特菌刺激的脾细胞培养物中可溶性TNF-α的产生，药物治疗降低了感染小鼠的血清TNF-α水平，而该化合物对干扰素-γ和白细胞介素-10的产生调节无效。KB-R7785的作用被认为依赖于TNF-α，因为该药物在抗TNF-α单克隆抗体处理的小鼠和TNF-α基因敲除小鼠中未能影响单核细胞增生李斯特菌感染。抗CD95L单克隆抗体对感染也无效。这些结果表明，在MMP抑制剂治疗的宿主中应考虑TNF-α对宿主抵抗力至关重要的传染病的诱导情况。
