Cleavage of Mitogen-Activated Protein Kinases in Human Neutrophils Undergoing Apoptosis: Role in Decreased Responsiveness to Inflammatory Cytokines1
Cleavage of Mitogen-Activated Protein Kinases in Human Neutrophils Undergoing Apoptosis: Role in Decreased Responsiveness to Inflammatory Cytokines1
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正在经历凋亡的人中性粒细胞中丝裂原激活蛋白激酶的裂解：在炎症细胞因子反应性降低中的作用1
作者：
Kenichi Suzuki;T. Hasegawa;C. Sakamoto;Yueqin Zhou;F. Hato;M. Hino;N. Tatsumi;S. Kitagawa
细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）是细胞因子刺激下人中性粒细胞活化的主要信号分子。这两种分子在中性粒细胞的N-末端部分裂解，中性粒细胞通过单独体外培养或用TNF和/或放线菌酮治疗诱导凋亡。G-CSF和半胱天冬酶抑制剂苄氧羰基-Val-Ala-Asp-fluoromethylketone可抑制这两种分子的裂解，这两种物质都能抑制中性粒细胞凋亡。在无细胞体系中，ERK和p38 MAPK不被重组caspase-3或caspase-8裂解，而凝溶胶蛋白在相同条件下被caspase-3裂解。这两种分子的裂解似乎对成熟中性粒细胞具有特异性，因为在经历细胞凋亡的未成熟细胞（HL-60和Jurkat）中未检测到，这表明负责这两种分子裂解的蛋白酶可能在分化成成熟中性粒细胞期间发展。随着ERK和p38 MAPK的裂解，GM-CSF和TNF诱导的超氧化物释放，粘附，ERK和p38 MAPK的磷酸化在中性粒细胞凋亡过程中减少。此外，GM-CSF和TNF诱导的超氧化物释放和粘附被PD 98059 MAPK/ERK激酶抑制剂以及SB 203580（p38 MAPK抑制剂）抑制，这表明ERK和p38 MAPK可能参与这些细胞因子诱导的超氧化物释放和粘附。这些研究结果表明，ERK和p38 MAPK的切割和降解的中性粒细胞经历凋亡的半胱天冬酶依赖性的方式和这两种分子的切割可能是部分负责降低功能反应性炎症细胞因子。
Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) are major signaling molecules activated in human neutrophils stimulated by cytokines. Both molecules were cleaved at the N-terminal portion in neutrophils undergoing apoptosis induced by in vitro culture alone or treatment with TNF and/or cycloheximide. The cleavage of both molecules was inhibited by G-CSF and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a caspase inhibitor, both of which can inhibit neutrophil apoptosis. In a cell-free system, ERK and p38 MAPK were not cleaved by recombinant caspase-3 or caspase-8 while gelsolin was cleaved by caspase-3 under the same condition. The cleavage of both molecules appears to be specific to mature neutrophils, since it was not detected in immature cells (HL-60 and Jurkat) undergoing apoptosis, indicating that proteases responsible for the cleavage of both molecules may develop during differentiation into mature neutrophils. Concomitant with the cleavage of ERK and p38 MAPK, GM-CSF- and TNF-induced superoxide release, adherence, and phosphorylation of ERK and p38 MAPK were decreased in neutrophils undergoing apoptosis. In addition, GM-CSF- and TNF-induced superoxide release and adherence were inhibited by PD98059 MAPK/ERK kinase inhibitor) as well as SB203580 (p38 MAPK inhibitor), suggesting possible involvement of ERK and p38 MAPK in superoxide release and adherence induced by these cytokines. These findings indicate that ERK and p38 MAPK are cleaved and degraded in neutrophils undergoing apoptosis in a caspase-dependent manner and the cleavage of both molecules may be partly responsible for decreased functional responsiveness to inflammatory cytokines.
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影响因子：
3.9
作者：
J. Benna;J. Benna;Jiahuai Han;Jiahuai Han;J. Park;J. Park;Elmar Schmid;Elmar Schmid;
通讯作者：
J. Benna;J. Benna;Jiahuai Han;Jiahuai Han;J. Park;J. Park;Elmar Schmid;Elmar Schmid;
影响因子：
56.9
作者：
Rudel, T;Bokoch, GM
通讯作者：
Bokoch, GM
Caspases 介导肿瘤坏死因子-α 诱导的中性粒细胞凋亡和活性氧产生的下调。
影响因子：
20.3
作者：
Yamashita,K;Takahashi,A;Kobayashi,S;Hirata,H;MesnerJr,PW;Kaufmann,SH;Yonehara,S;Yamamoto,K;Uchiyama,T;Sasada,M
通讯作者：
Sasada,M
影响因子：
20.3
作者：
Mansfield, PJ;Shayman, JA;Boxer, LA
通讯作者：
Boxer, LA
纯化的集落刺激因子可增强人中性粒细胞和嗜酸性粒细胞的体外存活：一种快速、灵敏的集落刺激因子微量测定法。
影响因子：
20.3
作者：
Begley,CG;Lopez,AF;Nicola,NA;Warren,DJ;Vadas,MA;Sanderson,CJ;Metcalf,D
通讯作者：
Metcalf,D