Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation
Inducible NOS-induced chloride intracellular channel 4 (CLIC4) nuclear translocation regulates macrophage deactivation
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DOI：
10.1073/pnas.1201351109
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发表时间：
2012-04-17
影响因子：
11.1
通讯作者：
Yuspa, Stuart H.
中科院分区：
文献类型：
--
作者：
Malik, Mariam;Jividen, Kasey;Yuspa, Stuart H.
细胞质CLIC 4的核转位是其促凋亡和促分化功能的基本特征。在这里，我们表明，CLIC 4诱导同时诱导诱导型一氧化氮合酶（iNOS）和S-亚硝基化的促炎性腹腔巨噬细胞。iNOS的化学抑制或基因消融抑制CLIC 4的S-亚硝基化和核转位。在巨噬细胞中，iNOS诱导的核CLIC 4与细胞的原抗炎转变一致，因为在CLIC 4和iNOS敲除的巨噬细胞中IL-1 β和CXCL 1 mRNA在晚期时间点保持升高，而TNF α mRNA仅在iNOS敲除的巨噬细胞中升高。活性IL-1 β在CLIC 4敲除巨噬细胞和其中CLIC 4核转位被NOS抑制剂L-NAME阻止的巨噬细胞中保持升高。此外，核靶向CLIC 4的过表达下调了刺激的巨噬细胞中的IL-1 β。在CLIC 4基因无效的小鼠中，LPS刺激的吞噬巨噬细胞的数量减少。因此，iNOS诱导的核CLIC 4是巨噬细胞失活程序的重要组成部分。
Nuclear translocation of cytosolic CLIC4 is an essential feature of its proapoptotic and prodifferentiation functions. Here we demonstrate that CLIC4 is induced concurrently with inducible nitric oxide synthase (iNOS) and S-nitrosylated in proinflammatory peritoneal macrophages. Chemical inhibition or genetic ablation of iNOS inhibits S-nitrosylation and nuclear translocation of CLIC4. In macrophages, iNOS-induced nuclear CLIC4 coincides with the proto anti-inflammatory transition of the cells because IL-1 beta and CXCL1 mRNA remain elevated in CLIC4 and iNOS knockout macrophages at late time points, whereas TNF alpha mRNA is elevated only in the iNOS knockout macrophages. Active IL-1 beta remains elevated in CLIC4 knockout macrophages and in macrophages in which CLIC4 nuclear translocation is prevented by the NOS inhibitor L-NAME. Moreover, overexpression of nuclear-targeted CLIC4 down-regulates IL-1 beta in stimulated macrophages. In mice, genetically null for CLIC4, the number of phagocytosing macrophages stimulated by LPS is reduced. Thus, iNOS-induced nuclear CLIC4 is an essential part of the macrophage deactivation program.