Tumor suppressor death-associated protein kinase is required for full IL-1β production
Tumor suppressor death-associated protein kinase is required for full IL-1β production
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DOI：
10.1182/blood-2010-08-303115
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发表时间：
2011-01-20
期刊：
影响因子：
20.3
通讯作者：
Lai, Ming-Zong
中科院分区：
文献类型：
--
作者：
Chuang, Ya-Ting;Lin, Yu-Chuan;Lai, Ming-Zong
白细胞介素-1 β（IL-1 β）对炎症和感染控制至关重要。IL-1 β的产生依赖于由炎症刺激诱导的pro-IL-1 β和炎性体组分的表达，随后炎性体组装以产生用于切割pro-IL-1 β的半胱天冬酶-1。在这里，我们表明，肿瘤抑制死亡相关蛋白激酶（DAPK）缺陷损害巨噬细胞IL-1 β的生产。相反，巨噬细胞中肿瘤坏死因子-α的产生不受DAPK敲除的影响。在DAPK缺陷的巨噬细胞中发现了IL-1 β产生的两层缺陷：一些刺激物引起的pro-IL-1 β诱导减少和所有检查的炎性刺激物引起的caspase-1活化减少。在DAPK缺陷型巨噬细胞中正常NLRP 3诱导的情况下，减少的半胱天冬酶-1生成归因于受损的炎性小体组装。存在DAPK与NLRP 3的直接结合，表明DAPK参与炎性小体形成。我们进一步证明，炎症信号诱导的NLRP 3炎性体原位形成因DAPK缺乏而受到损害。综上所述，我们的研究结果确定DAPK作为IL-1 β的完全产生和NLRP 3炎性体的功能组装所需的分子。此外，DAPK敲除减少了尿酸晶体触发的腹膜炎，这表明DAPK可以作为治疗IL-1 β相关自身炎症性疾病的靶点。（血。2011; 117（3）：960-970）
Interleukin-1 beta (IL-1 beta) is critical for inflammation and control of infection. The production of IL-1 beta depends on expression of pro-IL-1 beta and inflammasome component induced by inflammatory stimuli, followed by assembly of inflammasome to generate caspase-1 for cleavage of pro-IL-1 beta. Here we show that tumor suppressor death-associated protein kinase (DAPK) deficiency impaired IL-1 beta production in macrophages. Generation of tumor necrosis factor-alpha in macrophages, in contrast, was not affected by DAPK knockout. Two tiers of defects in IL-1 beta generation were found in DAPK-deficient macrophages: decreased pro-IL-1 beta induction by some stimuli and reduced caspase-1 activation by all inflammatory stimuli examined. With a normal NLRP3 induction in DAPK-deficient macrophages, the diminished caspase-1 generation is attributed to impaired inflammasome assembly. There is a direct binding of DAPK to NLRP3, suggesting an involvement of DAPK in inflammasome formation. We further illustrated that the formation of NLRP3 inflammasome in situ induced by inflammatory signals was impaired by DAPK deficiency. Taken together, our results identify DAPK as a molecule required for full production of IL-1 beta and functional assembly of the NLRP3 inflammasome. In addition, DAPK knockout reduced uric acid crystal-triggered peritonitis, suggesting that DAPK may serve as a target in the treatment of IL-1 beta-associated autoinflammatory diseases. (Blood. 2011; 117(3): 960-970)