REGULATION OF MURINE MACROPHAGE EFFECTOR FUNCTIONS BY LIPOARABINOMANNAN FROM MYCOBACTERIAL STRAINS WITH DIFFERENT DEGREES OF VIRULENCE
REGULATION OF MURINE MACROPHAGE EFFECTOR FUNCTIONS BY LIPOARABINOMANNAN FROM MYCOBACTERIAL STRAINS WITH DIFFERENT DEGREES OF VIRULENCE
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DOI：
10.1128/iai.61.10.4173-4181.1993
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发表时间：
1993-10-01
影响因子：
3.1
通讯作者：
KRAHENBUHL, JL
中科院分区：
文献类型：
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作者：
ADAMS, LB;FUKUTOMI, Y;KRAHENBUHL, JL
阿拉伯脂甘露聚糖 (LAM) 是分枝杆菌细胞壁中主要的含阿拉伯糖和甘露糖的磷酸化脂多糖 (LPS)。分析了来自结核分枝杆菌强毒菌株 (Erdman) (LAM(Erdman)) 和减毒菌株 (H37Ra) (LAM(H37Ra) 以及麻风分枝杆菌（强毒分枝杆菌）的 LAM 制剂对各种巨噬细胞 (Mphi) 效应器功能的影响。LAM(H37Ra) 与革兰氏阴性 LPS 一样，表现出剂量依赖性能力诱导正常 Mphi 中肿瘤坏死因子 α (TNF-α) 的产生，而 Mphi 的γ干扰素 (IFN-γ) 引发大大增加了 TNF-α 的水平，然而，LAM(H37Ra) 的作用不受多粘菌素 B 的影响，这完全消除了 LPS (Erdman) 和来自麻风分枝杆菌的 LAM 的作用，而另一方面，几乎不诱导 TNF-α 的产生。通过逆转录聚合酶链式反应检测的 Mphi mRNA 显示，各种制剂诱导的 TNF-α mRNA 水平与检测到的 TNF-α 蛋白水平相关。有趣的是，LAM（H37Ra）和 LAM（Erdman）都可以阻断随后的 IFN-γ 和 LPS 诱导的 Mphi 激活，这是先前报道的 LAM 下调 Mphi 效应器功能的有效能力的衡量标准。 LAM(H37Ra) 和 LPS 在正常和 IFN-γ 引发的 Mphi 中均不产生 NO2- 的作用，而 LAM(Erdman) 只能在引发的 Mphi 中刺激 NO2- 的产生。然而，LAM(Erdman)的触发能力被抗TNF-α抗体消除，这表明LAM(Erdman)刺激了足够的TNF-α产生以驱动与宿主抵抗相关的Mphi功能，因此，分枝杆菌LAM是Mphi功能的有效调节剂，这一事实可能对分枝杆菌疾病产生重要影响。
Lipoarabinomannan (LAM) is the major arabinose- and mannose-containing phosphorylated lipopolysaccharide (LPS) in mycobacterial cell walls. LAM preparations from a virulent strain (Erdman) (LAM(Erdman)) and an attenuated strain (H37Ra) (LAM(H37Ra) of Mycobacterium tuberculosis, as well as from M. leprae (a virulent mycobacterium), were analyzed for their effects on various macrophage (Mphi) effector functions. LAM(H37Ra), like gram-negative LPS, exhibited a dose-dependent ability to induce tumor necrosis factor alpha (TNF-alpha) production in normal Mphi, and gamma interferon (IFN-gamma) priming of the Mphi greatly augmented the levels of TNF-alpha. However, the effects of LAM(H37Ra) were unaffected by polymyxin B, which totally abrogated the effects of LPS. LAM(Erdman) and LAM from M. leprae, on the other hand, induced virtually no TNF-alpha production. Analysis of Mphi mRNA by reverse transcription-polymerase chain reaction revealed that the levels of TNF-alpha mRNA induced by the various preparations correlated with the levels of TNF-alpha protein detected. Interestingly, both LAM(H37Ra) and LAM(Erdman) could block subsequent IFN-gamma- and LPS-induced Mphi activation, a previously reported measure of the potent ability of LAM to down-regulate Mphi effector functions. Two lines of evidence suggested, however, that Mphi cyclooxygenase products did not play a role in this down-regulation. LAM(H37Ra) and LPS could induce the production of NO2- in both normal and IFN-gamma-primed Mphi, whereas LAM(Erdman) could stimulate NO2- production only in primed Mphi. Both LAM(H37Ra) and LAM(Erdman) could substitute for LPS as a triggering signal for IFN-gamma-primed Mphi in a toxoplasma killing assay. The triggering ability Of LAM(Erdman), however, was abrogated by an anti-TNF-alpha antibody, suggesting that sufficient TNF-alpha production was stimulated by LAM(Erdman) to drive a Mphi function relevant in host resistance. Thus, mycobacterial LAM is a potent regulator of Mphi functions, a fact that may have important consequences in mycobacterial disease.