ADAM17 activity during human neutrophil activation and apoptosis
ADAM17 activity during human neutrophil activation and apoptosis
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DOI：
10.1002/eji.200535257
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发表时间：
2006-04-01
影响因子：
5.4
通讯作者：
DeLeo, FR
中科院分区：
文献类型：
--
作者：
Walcheck, B;Herrera, AH;DeLeo, FR
金属蛋白酶ADAM17(也称为肿瘤坏死因子-α转换酶或TACE)的底物经历胞外结构域脱落，并包括各种炎症调节剂。尽管多形核白细胞在炎症中起重要作用，但ADAM17在人中性粒细胞上的直接分析非常有限。此外，目前对调节ADAM17活性的过程的理解主要与其快速激活有关。因此，为了进一步深入了解ADAM17的活性机制，我们研究了其表面表达及其底物在中性粒细胞激活和凋亡延长期间的脱落。与永生化造血细胞系的研究相反，我们报告了ADAM17的表面表达是通过甲酰肽激活的人中性粒细胞或通过FCR/补体受体介导的吞噬来维持的。有趣的是，细菌吞噬作用导致ADAM17的表达在病原体吞噬几小时后显著增加。我们提供了新的证据，在自发和抗Fas诱导的中性粒细胞凋亡过程中，ADAM17的表面表达也保持不变。在每种测试条件下，中性粒细胞都能有效地释放经过验证的ADAM17底物L-选择素和原肿瘤坏死因子-α。因此，我们的数据表明，在中性粒细胞效应器功能过程中，ADAM17的表达延长。这可能意味着ADAM17在诱导和下调中性粒细胞活性方面发挥了作用。
Substrates of the metalloprotease ADAM17 (also known as TNF-alpha converting enzyme or TACE) undergo ectodomain shedding and include various inflammatory modulators. Though polymorphonuclear leukocytes contribute significantly to inflammation, direct analyses of ADAM17 on human neutrophils are very limited. In addition, the current understanding of the processes regulating ADAM17 activity primarily relate to its rapid activation. Therefore, to extend insights into the mechanisms of ADAM17 activity, we examined its surface expression and the shedding of its substrates during extended periods of neutrophil activation and apoptosis. Contrary to studies with immortalized hematopoietic cell lines, we report that surface expression of ADAM17 is maintained by human neutrophils activated with formyl peptides or by FcR/complement receptor-mediated phagocytosis. Interestingly, bacterial phagocytosis resulted in a significant increase in ADAM17 expression several hours after pathogen engulfment. We provide novel evidence that ADAM17 surface expression is also maintained during spontaneous and anti-Fas-induced neutrophil apoptosis. The well-validated ADAM17 substrates L-selectin and proTNF-alpha were shed efficiently by neutrophils under each of the conditions tested. Our data thus indicate prolonged ADAM17 expression during neutrophil effector functions. The implications of this may be a role by ADAM17 in both the induction and down-regulation of neutrophil activity.