Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis
Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis
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DOI：
10.1016/s1097-2765(03)00056-x
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发表时间：
2003-03-01
期刊：
影响因子：
16
通讯作者：
Kastner, DL
中科院分区：
文献类型：
--
作者：
Chae, JJ;Komarow, HD;Kastner, DL
家族性地中海热（FMF）是一种遗传性疾病，其特征是反复发作的发热和炎症。大多数患有FMF的患者在pyrin蛋白的C末端的一半中携带错义突变。为了研究pyrin的生理作用，我们产生了表达截短的pyrin分子的小鼠，其类似于FMF患者，保留了完整的PYRIN结构域。细菌脂多糖（LPS）诱导纯合子突变小鼠的体温升高和致死率增加。当受到刺激时，这些小鼠的巨噬细胞产生大量活化的半胱天冬酶-1，从而提高成熟IL-1 β的水平。全长pyrin在体外与半胱天冬酶-1竞争结合ASC，ASC是一种已知的半胱天冬酶-1激活剂。通过IL-1非依赖性途径，在来自芘截短小鼠的巨噬细胞中细胞凋亡受损。这些数据支持的先天性免疫反应中的关键作用，可能是通过对ASC的作用，并建议在人类中的选择的低形态的pyrin变体的生物学基础。
Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent episodes of fever and inflammation. Most patients with FMF carry missense mutations in the C-terminal half of the pyrin protein. To study the physiologic role of pyrin, we generated mice expressing a truncated pyrin molecule that, similar to FMF patients, retains the full PYRIN domain. Bacterial lipopolysaccharide (LPS) induces accentuated body temperatures and increased lethality in homozygous mutant mice. When stimulated, macrophages from these mice produce increased amounts of activated caspase-1 and, consequently, elevated levels of mature IL-1beta. Full-length pyrin competes in vitro with caspase-1 for binding to ASC, a known caspase-1 activator. Apoptosis is impaired in macrophages from pyrin-truncation mice through an IL-1-independent pathway. These data support a critical role for pyrin in the innate immune response, possibly by acting on ASC, and suggest a biologic basis for the selection of hypomorphic pyrin variants in man.