Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin
Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin
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DOI：
10.1038/sj.cdd.4401264
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发表时间：
2003-09-01
影响因子：
12.4
通讯作者：
Porter, AG
中科院分区：
文献类型：
--
作者：
Hentze, H;Lin, XY;Porter, AG
钾离子载体尼日利亚菌素诱导细胞死亡，并促进脂多糖（LPS）致敏的单核细胞和巨噬细胞中IL-1 β的成熟和释放，后者依赖于caspase-1的激活，其机制未知。在这里，我们研究触发细胞死亡和激活caspase-1的途径。我们发现，没有LPS引发，尼日利亚菌素单独触发caspase-1激活和IL-18的产生在THP-1单核细胞。同时，尼日利亚菌素诱导caspase-1非依赖性坏死细胞死亡，这被组织蛋白酶B抑制剂CA-074-Me和其他组织蛋白酶抑制剂阻断。尼日利亚菌素处理后的组织蛋白酶B活化通过生物化学测定，并通过快速溶酶体渗漏和组织蛋白酶B易位至细胞质证实。在THP-1细胞、原代小鼠巨噬细胞和人血单核细胞中，胱天蛋白酶-1和组织蛋白酶B抑制剂均阻止IL-18成熟。此外，IL-18的产生减少在THP-1细胞中稳定转化的半胱氨酸蛋白酶抑制剂A（内源性组织蛋白酶抑制剂）或反义组织蛋白酶B cDNA。总的来说，我们的研究确定了组织蛋白酶B在尼日利亚菌素诱导的caspase-1依赖性IL-18成熟和caspase-1非依赖性坏死中的关键作用。
The potassium ionophore nigericin induces cell death and promotes the maturation and release of IL-1beta in lipopolysaccharide (LPS)-primed monocytes and macrophages, the latter depending on caspase-1 activation by an unknown mechanism. Here, we investigate the pathway that triggers cell death and activates caspase-1. We show that without LPS priming, nigericin alone triggered caspase-1 activation and IL-18 generation in THP-1 monocytic cells. Simultaneously, nigericin induced caspase-1-independent necrotic cell death, which was blocked by the cathepsin B inhibitor CA-074-Me and other cathepsin inhibitors. Cathepsin B activation after nigericin treatment was determined biochemically and corroborated by rapid lysosomal leakage and translocation of cathepsin B to the cytoplasm. IL-18 maturation was prevented by both caspase-1 and cathepsin B inhibitors in THP-1 cells, primary mouse macrophages and human blood monocytes. Moreover, IL-18 generation was reduced in THP-1 cells stably transformed either with cystatin A ( an endogenous cathepsin inhibitor) or antisense cathepsin B cDNA. Collectively, our study establishes a critical role for cathepsin B in nigericin-induced caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis.