Müller M, Althaus R, Fröhlich D, Frei K, Eugster H P
Novartis Pharma Research Basel, Switzerland.
Eur J Immunol. 1999 Oct;29(10):3089-97. doi: 10.1002/(SICI)1521-4141(199910)29:10<3089::AID-IMMU3089>3.0.CO;2-D.
Mice deficient for TNF ligand and receptor type 1 have demonstrated the importance of TNF in the host defense against Listeria monocytogenes. To investigate the particular deficiency of macrophages derived from TNF/lymphotoxin (LT)-alpha(-/-) mice in antilisterial growth control, bone marrow-derived macrophages (BMDM) were used for in vitro infection experiments. After the combined treatment with IFN-gamma and lipopolysaccharide (LPS), production of NO by wild-type (wt) and TNF/LT-alpha(-/-) BMDM was induced to comparable levels, but only wt BMDM controlled L. monocytogenes growth efficiently. Nevertheless, inhibition of NO production led to a remarkable loss of antilisterial activity. This suggests that presence of NO is necessary but not sufficient for L. monocytogenes killing and that elimination of L. monocytogenes requires additional effector molecules. The LPS-inducible superoxide production of TNF/LT-alpha(-/-) BMDM was impaired. Accordingly both scavenging of superoxide and peroxynitrite led to reduced L. monocytogenes killing by wt BMDM. In addition, peroxynitrite was able to kill L. monocytogenes in vitro. Together these findings suggest that the defective host defense of TNF/LT-alpha-deficient mice against L. monocytogenes partially stems from reduced superoxide production of macrophages due to the absence of TNF and imply a function for peroxynitrite, the reaction product of NO and superoxide, in the intracellular killing of L. monocytogenes.
缺乏肿瘤坏死因子（TNF）配体和1型受体的小鼠已证明TNF在宿主抵御单核细胞增生李斯特菌的防御中具有重要作用。为了研究源自TNF/淋巴毒素（LT）-α（-/-）小鼠的巨噬细胞在抗李斯特菌生长控制方面的特定缺陷，使用骨髓来源的巨噬细胞（BMDM）进行体外感染实验。在用干扰素-γ和脂多糖（LPS）联合处理后，野生型（wt）和TNF/LT-α（-/-）BMDM的一氧化氮（NO）产生被诱导至相当水平，但只有wt BMDM能有效地控制单核细胞增生李斯特菌的生长。然而，抑制NO产生导致抗李斯特菌活性显著丧失。这表明NO的存在对于杀死单核细胞增生李斯特菌是必要的，但不是充分的，并且消除单核细胞增生李斯特菌需要额外的效应分子。TNF/LT-α（-/-）BMDM的LPS诱导的超氧化物产生受损。相应地，超氧化物和过氧亚硝酸盐的清除都导致wt BMDM对单核细胞增生李斯特菌的杀伤减少。此外，过氧亚硝酸盐能够在体外杀死单核细胞增生李斯特菌。这些发现共同表明，TNF/LT-α缺陷小鼠对单核细胞增生李斯特菌的宿主防御缺陷部分源于由于缺乏TNF导致巨噬细胞超氧化物产生减少，并暗示过氧亚硝酸盐（NO和超氧化物的反应产物）在细胞内杀死单核细胞增生李斯特菌中具有作用。
