Converting enzyme-independent release of tumor necrosis factor α and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3
Converting enzyme-independent release of tumor necrosis factor α and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3
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DOI：
10.1073/pnas.96.11.6261
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发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
Cheronis, J
中科院分区：
文献类型：
--
作者：
Coeshott, C;Ohnemus, C;Cheronis, J
介导炎症的两种重要细胞因子是肿瘤坏死因子cu （TNF α）和IL-1 β，两者都需要通过转化酶转化为可溶性形式。TNF α转化酶和il -lp转化的重要性。特异性转化酶抑制剂的使用已经证明了循环中产生TNF α和IL-1 β的酶对系统性挑战的反应。然而，许多炎症反应不是全身性的，而是局部性的。在这些情况下，细胞因子的释放和/或激活可能不同于对全身刺激的反应，特别是因为这些病灶中各种细胞群的关联允许原细胞因子暴露于活化的中性粒细胞、中性粒细胞弹性酶（NE）、蛋白酶3 （PR3）和组织蛋白酶G （Cat G）产生的蛋白水解酶。为了研究中性粒细胞衍生的蛋白酶对TNF α和/或IL-1 β的替代加工的可能性，在活化的人中性粒细胞存在的情况下，测量脂多糖刺激的THP-1细胞的免疫反应性TNF α和IL-1 β释放。在这些条件下，TNFa和IL-1 β的释放增加了2至5倍。在NE和PR3的特异性抑制剂存在下，这两种细胞因子的增强释放在很大程度上被消除；然而，在NE和Cat G选择性抑制剂，分泌性白细胞蛋白酶抑制剂的存在下，增强释放的减少是最小的。这一发现表明，PR3而不是NE或Cat g的释放增加，纯化酶的使用证实了这一结论。这些结果表明，这两种促炎细胞因子的产生可能有其他途径，特别是在局部炎症过程中。
Two important cytokines mediating inflammation are tumor necrosis factor cu (TNF alpha) and IL-1 beta, both of which require conversion to soluble forms by converting enzymes. The importance of TNF alpha-converting enzyme and IL-lp-converting. enzyme in the production of circulating TNF alpha and IL-1 beta in response to systemic challenges has been demonstrated by the use of specific converting enzyme inhibitors. Many inflammatory responses, however, are not systemic but instead are localized. In these situations release and/or activation of cytokines may be different from that seen in response to a systemic stimulus, particularly because associations of various cell populations in these foci allows for the exposure of procytokines to the proteolytic enzymes produced by activated neutrophils, neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (Cat G), To investigate the possibility of alternative processing of TNF alpha and/or IL-1 beta by neutrophil-derived proteinases, immunoreactive TNF alpha and IL-1 beta release from lipopolysaccharide-stimulated THP-1 cells was measured in the presence of activated human neutrophils. Under these conditions, TNFa and IL-1 beta release was augmented 2- to 5-fold. In the presence of a specific inhibitor of NE and PR3, enhanced release of both cytokines was largely abolished; however, in the presence of a NE and Cat G selective inhibitor, secretory leucocyte proteinase inhibitor, reduction of the enhanced release was minimal. This finding suggested that the augmented release was attributable to PR3 but not NE nor Cat G. Use of purified enzymes confirmed this conclusion. These results indicate that there may be alternative pathways for the production of these two proinflammatory cytokines, particularly in the context of local inflammatory processes.