Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells
Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells
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DOI：
10.1182/blood-2006-07-033597
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Miyachi, Yoshiki
中科院分区：
文献类型：
--
作者：
Fujisawa, Akihiro;Kambe, Naotomo;Miyachi, Yoshiki
冷诱导自身炎性综合征1（CIAS 1）基因突变与一系列自身炎性疾病相关，包括家族性冷自身炎性综合征、Muckle-Wells综合征和慢性婴儿神经、皮肤、关节综合征，也称为脑源性多系统炎性疾病。CIAS 1编码cryopyrin，一种定位于细胞溶质并作为模式识别受体发挥功能的蛋白质。Cryopyrin还参与核因子-κ B调节和caspase-1介导的白细胞介素1 R成熟。在这项研究中，我们发现CIAS 1中的疾病相关突变诱导THP-1单核细胞的快速细胞死亡。细胞死亡的特征，包括7-AAD染色，细胞水肿的存在，以及导致乳酸脱氢酶（LDH）释放的早期膜损伤，表明其更可能是坏死而不是凋亡，并且被组织蛋白酶B特异性抑制剂CA-074-Me有效地阻断。CA-074-Me还抑制由疾病相关突变诱导的溶酶体渗漏和线粒体损伤。此外，最近鉴定的cryopyrin相关炎性体的激活剂R837在野生型CIAS 1转染的THP-1细胞中诱导细胞死亡。这些结果表明，单核细胞在cryopyrin激活时以组织蛋白酶B依赖性方式经历快速细胞死亡，这也是由CIAS 1的疾病相关突变诱导的特定现象。
Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-kappa B regulation and caspase-1-mediated maturation of interleukin 1 R. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.