IFN-gamma-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-alpha.
IFN-gamma-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-alpha.
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DOI：
10.4049/jimmunol.148.2.568
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发表时间：
1992-01
影响因子：
4.4
通讯作者：
J. Langermans;M. E. B. Hulst;P. Nibbering;P. S. Hiemstra;L. Fransen;R. V. Furth
中科院分区：
文献类型：
--
作者：
J. Langermans;M. E. B. Hulst;P. Nibbering;P. S. Hiemstra;L. Fransen;R. V. Furth
活化的小鼠腹腔巨噬细胞抑制刚地弓形虫的细胞内增殖并产生许多细胞因子，如TNF-α和IL-1。据报道，TNF-α和IL-1都参与了针对各种微生物的免疫应答，但这些作用的机制尚不清楚。在本研究中，研究了内源性产生的TNF-α和IL-1是否参与rIFN-γ激活腹腔巨噬细胞，导致弓形虫抑制活性和活性氮中间体的产生。rIFN-γ诱导的弓形虫抑制活性被抗小鼠TNF-α的中和抗体以剂量依赖性和时间依赖性方式抑制，但抗小鼠IL-1 α和IL-1 β的中和抗体不影响该活性。TNF-α参与弓形虫抑制活性的诱导，我们的发现证实了rTNF-α与非活化浓度的rIFN-γ联合抑制T细胞的细胞内增殖。刚地。rIL-1和rIFN-γ对T. rTNF-α和rIL-1 α单独作用可抑制弓形虫细胞内的增殖。只是轻微感染因为最近有报道说，活化的巨噬细胞产生的活性氮中间体，是必不可少的诱导弓形虫的抑制活性，我们调查这些中间体是否参与了TNF-依赖诱导弓形虫的抑制活性。针对小鼠TNF-α的中和抗体也几乎完全抑制rIFN-γ激活的巨噬细胞释放NO2-。巨噬细胞与rTNF-α和非活化浓度的rIFN-γ共同孵育可释放大量的NO2-，但rTNF-α和rIL-1 α单独孵育，rIL-1 α和非活化浓度的rIFN-γ共同孵育仅诱导巨噬细胞释放少量NO2-。探讨活性氮中间产物对T.将巨噬细胞与L-精氨酸类似物NG-单甲基-L-精氨酸或NADPH抑制剂二亚苯基碘鎓一起孵育，这两种抑制剂都能抑制活性氮中间体的产生。在T.弓形虫感染巨噬细胞后，NO_2 ~-的释放与弓形虫的抑制活性无相关性。（400字处截断摘要）
Activated murine peritoneal macrophages inhibit the intracellular proliferation of Toxoplasma gondii and produce a number of cytokines, such as TNF-alpha and IL-1. Both TNF-alpha and IL-1 have been reported to be involved in the immune response against various microorganisms, but the mechanisms responsible for these effects are not known. In the present study it was investigated whether endogenously produced TNF-alpha and IL-1 are involved in the activation of peritoneal macrophages by rIFN-gamma leading to toxoplasmastatic activity and the production of reactive nitrogen intermediates. The rIFN-gamma-induced toxoplasmastatic activity was inhibited by neutralizing antibodies against mouse TNF-alpha in a dose-dependent and time-dependent way, but neutralizing antibodies against mouse IL-1 alpha and IL-1 beta did not affect this activity. Involvement of TNF-alpha in the induction of toxoplasmastatic activity was confirmed by our finding that rTNF-alpha in combination with a nonactivating concentration of rIFN-gamma inhibited the intracellular proliferation of T. gondii. No synergistic activity of rIL-1 and rIFN-gamma on the inhibition of T. gondii proliferation was found. Both rTNF-alpha and rIL-1 alpha alone inhibited the intracellular proliferation of T. gondii only slightly. Because it has been reported recently that activated macrophages produce reactive nitrogen intermediates that are essential in the induction of toxoplasmastatic activity, we investigated whether these intermediates are involved in the TNF-dependent induction of toxoplasmastatic activity. Neutralizing antibodies against mouse TNF-alpha inhibited also the release of NO2- by rIFN-gamma-activated macrophages almost completely. Macrophages incubated with rTNF-alpha in combination with a nonactivating concentration of rIFN-gamma released substantial amounts of NO2-, but rTNF-alpha and rIL-1 alpha alone, and the combination of rIL-1 alpha and a nonactivating concentration of rIFN-gamma induced only little NO2(-)-release by macrophages. To assess whether reactive nitrogen intermediates act directly or indirectly on the intracellular proliferation of T. gondii, macrophages were incubated with the L-arginine analog NG-monomethyl-L-arginine or the NADPH-inhibitor diphenylene iodonium, both inhibitors of the generation of reactive nitrogen intermediates. Good correlation was found between toxoplasmastatic activity and the release of NO2- during the 24-h activation period before infection of the macrophages with T. gondii, but no correlation was found between toxoplasmastatic activity and the release of NO2- during infection of the macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)