Mechanism by which U937 promonocytic cells inactivate human interferon-gamma.
Mechanism by which U937 promonocytic cells inactivate human interferon-gamma.
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U937 早单核细胞灭活人干扰素-γ 的机制。
DOI：
10.1089/jir.1995.15.557
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Parmely,MJ
中科院分区：
文献类型：
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作者：
Duval-Jobe,C;Leeson,M;Rawitch,A;Parmely,MJ
单核吞噬细胞产生被认为在调节细胞因子活性中起作用的蛋白酶。活化的巨噬细胞分泌尿激酶型纤溶酶原激活剂（uPA），它介导从普遍存在的纤溶酶原酶原形成丝氨酸蛋白酶纤溶酶。我们之前观察到原单核细胞U937对纤溶酶原的激活与这些细胞通过蛋白水解使重组干扰素-γ(rIFN-γ)失活的明显能力之间存在相关性。本研究旨在验证U937细胞培养中产生的纤溶蛋白是通过有限的蛋白水解使rIFN-γ失活的必要和充分的假设。以下观察结果与这一假设一致：(1)丝氨酸蛋白酶抑制剂或特异性降低纤溶酶活性的抗体可以阻止rIFN-γ的失活；(2)纯化的纤溶蛋白灭活rIFN-γ的效率与U937培养上清一样高，对丝氨酸蛋白酶抑制剂同样敏感；(3)纤溶酶从rIFN-γ中去除一个11个氨基酸的羧基末端肽，其中包括一个已知的生物活性所必需的区域。总的来说，这些数据表明，纤溶酶原被U937前体细胞激活导致IFN-γ的蛋白水解失活，这一过程只需要产生纤溶酶。
Mononuclear phagocytes produce proteinases that are thought to play a role in regulating the activity of cytokines. Activated macrophages secrete urokinase-type plasminogen activator (uPA), which mediates the formation of the serine proteinase plasmin from the ubiquitous zymogen plasminogen. We previously observed a correlation betweenin vitroplasminogen activation by the promonocytic cell line U937 and the apparent ability of these cells to inactivate recombinant interferon-γ(rIFN-γ) by proteolysis. The present study was designed to test the hypothesis that plasmin, generated in U937 cell cultures, is both necessary and sufficient to inactivate rIFN-γ by limited proteolysis. The following observations are consistent with this hypothesis: (1) inactivation of rIFN-γ was prevented by inhibitors of serine proteinases or an antibody that specifically immunodepleted plasmin activity; (2) purified plasmin inactivated rIFN-γ as efficiently as U937 culture supernatants and was similarly sensitive to serine proteinase inhibitors; and (3) plasmin removed an 11 amino acid carboxyl-terminal peptide from rIFN-γ, which included a region known to be required for bioactivity. Overall, these data indicate that plasminogen activation by U937 promonocytic cells leads to the proteolytic inactivation of IFN-γ by a process that only requires the production of plasmin.