Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases.
Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases.
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DOI：
10.4049/jimmunol.161.12.6648
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发表时间：
1998-12
影响因子：
4.4
通讯作者：
R. Trotta;Kristin A. Puorro;M. Paroli;L. Azzoni;Bekele Abebe;L. Eisenlohr;B. Perussia
中科院分区：
文献类型：
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作者：
R. Trotta;Kristin A. Puorro;M. Paroli;L. Azzoni;Bekele Abebe;L. Eisenlohr;B. Perussia
细胞外信号调节蛋白激酶(ERK，又称丝裂原激活蛋白激酶)是一种丝氨酸-苏氨酸激酶，通过与多种酪氨酸激酶相关受体的配体结合而传递信号。我们已经报道，ERK2的磷酸化和激活伴随着NK细胞上免疫球蛋白Fc部分的低亲和力受体(CD16)的结合，并且是CD16诱导的TNF-αmRNA表达所必需的。在这里，我们分析了ERK在NK细胞介导的细胞毒作用和靶细胞刺激后诱导的干扰素-γ表达中的作用，无论靶细胞是否包被抗体。我们的数据表明，与免疫复合体一样，当人类原代NK细胞与颗粒胞吐介导的自发细胞毒性敏感的靶细胞相互作用时，ERK2磷酸化发生，这调节了靶细胞和免疫复合体诱导的细胞毒性和干扰素-γ的mRNA表达。丝裂原活化蛋白激酶的特异性抑制剂以剂量依赖的方式降低自发和抗体依赖的细胞毒性，至少部分地抑制颗粒胞吐，而不影响效应器/靶细胞的相互作用和细胞骨架蛋白肌动蛋白和微管蛋白的重排。利用遗传方法，在感染编码ERK失活突变体的重组痘苗病毒的原代NK细胞中，证实了ERK参与了钙依赖细胞介导的细胞毒性的调节。这些数据表明，NK细胞在与负责自发或依赖于抗体的靶细胞识别的受体结合时所引发的生化途径，尽管是不同的，但利用ERK作为其下游分子之一来调节效应器功能。
Extracellular signal-regulated kinases (ERK, also known as mitogen-activated protein kinases) are serine-threonine kinases transducing signals elicited upon ligand binding to several tyrosine kinase-associated receptors. We have reported that ERK2 phosphorylation and activation follows engagement of the low affinity receptor for the Fc portion of IgG (CD16) on NK cells, and is necessary for CD16-induced TNF-alpha mRNA expression. Here, we analyzed the involvement of ERK in NK cell-mediated cytotoxicity and IFN-gamma expression induced upon stimulation with targets cells, coated or not with Abs. Our data indicate that, as with immune complexes, ERK2 phosphorylation occurs in human primary NK cells upon interaction with target cells sensitive to granule exocytosis-mediated spontaneous cytotoxicity, and that this regulates both target cell- and immune complex-induced cytotoxicity and IFN-gamma mRNA expression. A specific inhibitor of mitogen-activated protein kinase kinase reduced both spontaneous and Ab-dependent cytotoxicity in a dose-dependent manner involving, at least in part, inhibition of granule exocytosis without affecting effector/target cell interaction and rearrangement of the cytoskeleton proteins actin and tubulin. Involvement of ERK in the regulation of Ca2+-dependent cell-mediated cytotoxicity was confirmed, using a genetic approach, in primary NK cells infected with a recombinant vaccinia virus encoding an ERK inactive mutant. These data indicate that the biochemical pathways elicited in NK cells upon engagement of receptors responsible for either spontaneous or Ab-dependent recognition of target cells, although distinct, utilize ERK as one of their downstream molecules to regulate effector functions.