INHIBITION OF LEGIONELLA-PNEUMOPHILA GROWTH BY GAMMA-INTERFERON IN PERMISSIVE A/J MOUSE MACROPHAGES - ROLE OF REACTIVE OXYGEN SPECIES, NITRIC-OXIDE, TRYPTOPHAN, AND IRON(III)
INHIBITION OF LEGIONELLA-PNEUMOPHILA GROWTH BY GAMMA-INTERFERON IN PERMISSIVE A/J MOUSE MACROPHAGES - ROLE OF REACTIVE OXYGEN SPECIES, NITRIC-OXIDE, TRYPTOPHAN, AND IRON(III)
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DOI：
10.1128/iai.62.8.3197-3205.1994
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发表时间：
1994-08-01
影响因子：
3.1
通讯作者：
FRIEDMAN, H
中科院分区：
文献类型：
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作者：
GEBRAN, SJ;YAMAMOTO, Y;FRIEDMAN, H
感染嗜肺军团菌并用γ干扰素（IFN-γ）处理的A/J小鼠巨噬细胞在体外产生了有效的抗菌活性。这种抗军团菌活性与巨噬细胞产生活性氧中间体的能力无关，因为氧自由基清除剂过氧化氢酶、超氧化物歧化酶、甘露醇和硫脲对IFN-γ激活的巨噬细胞的抗军团菌活性没有影响。同样，虽然 IFN-γ 激活的巨噬细胞合成活性氮中间体的能力受到 L-精氨酸 (Arg) 类似物、N-G-单甲基-L-精氨酸和 L-氨基胍以及在不含 L-Arg 的培养基中培养的显着抑制，但它们抑制嗜肺军团菌细胞内生长的能力保持完整。细胞内经常生长。 A/J 巨噬细胞中的嗜肺军团菌可被铁 (III) 螯合剂去铁胺抑制，并被铁转铁蛋白和三价铁盐逆转。此外，与未激活的细胞相比，IFN-γ激活的巨噬细胞掺入的 Fe-59(III) 减少了 28%。尽管如此，当 IFN-γ 刺激的巨噬细胞被铁 (III) 饱和时，仅观察到生长限制的部分阻断。吲哚丙酸似乎可以抑制 L-色氨酸 (L-Trp) 的生物合成，通常是一种 L-Trp 可逆生长抑制剂。巨噬细胞中存在嗜肺军团菌，这意味着该病原体的细胞内复制也是 L-Trp 依赖性的。然而，过量的外源性 L-Trp 并不能逆转 IFN-γ 引起的生长抑制，尽管当培养基补充铁 (III) 和 L-Trp 时观察到小的协同效应。我们得出的结论是，IFN-γ激活的巨噬细胞通过活性氧中间体和活性氮中间体独立机制以及部分营养依赖性机制抑制嗜肺军团菌的细胞内增殖。我们还认为，可能还涉及其他尚不清楚的机制，因为从未获得完全逆转，并且因为在较高浓度的 IFN-γ 下，铁（III）不会诱导嗜肺军团菌生长抑制的任何显着逆转。
A/J mouse macrophages infected with Legionella pneumophila and treated with gamma interferon (IFN-gamma) in vitro developed potent antimicrobial activity. This antilegionella activity was independent of the macrophage capacity to generate reactive oxygen intermediates, since the oxygen radical scavengers catalase, superoxide dismutase, mannitol, and thiourea had no effect on the antilegionella activity of IFN-gamma-activated macrophages. Likewise, whereas the ability of IFN-gamma-activated macrophages to synthesize reactive nitrogen intermediates was markedly inhibited by the L-arginine (Arg) analogs, N-G-monomethyl-L-arginine and L-aminoguanidine, as well as by incubation in L-Arg-free medium, their ability to inhibit the intracellular growth of L. pneumophila remained intact. The intracellular growth oft. pneumophila in A/J macrophages was inhibited by the iron(III) chelator desferrioxamine and reversed by Fe-transferrin as well as by ferric salts. Additionally, IFN-gamma-activated macrophages incorporated 28% less Fe-59(III) compared, with nonactivated cells. Nonetheless, only partial blocking of growth restriction was observed when IFN-gamma-stimulated macrophages were saturated with iron(III). Indole-propionic acid, which appears to inhibit the biosynthesis of L-tryptophan (L-Trp), was an L-Trp-reversible growth inhibitor oft. pneumophila in macrophages, implying that the intracellular replication of this pathogen is also L-Trp dependent. However, an excess of exogenous L-Trp did not reverse the growth inhibition due to IFN-gamma, though a small synergistic effect was observed when the culture medium was supplemented with both iron(III) and L-Trp. We conclude that IFN-gamma-activated macrophages inhibit the intracellular proliferation of L. pneumophila by reactive oxygen intermediate- and reactive nitrogen intermediate-independent mechanisms and just partially by nutritionally dependent mechanisms. We also suggest that additional mechanisms, still unclear, may be involved, since complete reversion was never obtained and since at higher concentrations of IFN-gamma, iron(III) did not induce any significant reversion in the L. pneumophila growth inhibition.