Autoimmune inner ear disease patient-associated 28-kDa proinflammatory IL-1β fragment results from caspase-7-mediated cleavage in vitro.
Autoimmune inner ear disease patient-associated 28-kDa proinflammatory IL-1β fragment results from caspase-7-mediated cleavage in vitro.
复制标题
自身免疫性内耳疾病患者相关的 28 kDa 促炎性 IL-1β 片段由 caspase-7 介导的体外裂解产生。
DOI：
10.1172/jci.insight.130845
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发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Vambutas,Andrea
中科院分区：
文献类型：
--
作者：
Pathak,Shresh;Vambutas,Andrea
白细胞介素-1 β（IL-1β）是一种重要的促炎细胞因子，参与包括自身免疫性内耳病（AIED）在内的多种自身炎症和自身免疫性疾病的发生发展。IL-1β抑制剂已被证明可导致一小群皮质类固醇耐药AIED患者的临床听力改善。caspase-1对pro-IL-1β的典型加工产生一个活性17-kDa片段，能够引发促炎微环境。然而，在对LPS的反应中，与对照受试者的PBMC相比，AIED患者的PBMC独特地表达28-kDa的IL-1β片段。我们合成并比较了28-kDa片段与17-kDa IL-1β产物和pro-IL-1 31-kDa蛋白的生物活性。28-kDa IL-1β片段诱导PBMC中的IL-6、TNF-α和CCL 3。独特的是，只有胱天蛋白酶-7治疗显示出剂量和时间依赖性的增加，在28 kDa条带的产生。质谱法证实了pro-IL-1β的推定半胱天冬酶-7切割位点，其用于产生用于PBMC刺激研究的28-kDa片段。总的来说，这些结果提供了对AIED患者中一种知之甚少的、加工的28-kDa形式的IL-1β的功能的深入了解，该IL-1β由caspase-7独特地产生，并且能够激活进一步的下游促炎细胞因子。进一步的研究可能为治疗这种罕见疾病提供新的药理学靶点。
Interleukin-1β (IL-1β) is a key proinflammatory cytokine involved in the progression of many autoinflammatory and autoimmune diseases, including autoimmune inner ear disease (AIED). IL-1β inhibition has been shown to result in clinical hearing improvement in a small cohort of corticosteroid-resistant patients with AIED. Canonical processing of pro–IL-1β by caspase-1 generates an active 17-kDa fragment, capable of instigating a proinflammatory microenvironment. However, in response to LPS, PBMCs from patients with AIED uniquely express a 28-kDa IL-1β fragment, as compared with PBMCs from control subjects. We synthesized and compared the biologic activity of the 28-kDa fragment to the 17-kDa IL-1β product and the pro–IL-1 31-kDa protein. The 28-kDa IL-1β fragment induces IL-6, TNF-α, and CCL3 in PBMCs. Uniquely, only caspase-7 treatment showed a dose- and time-dependent increase in 28-kDa band generation. Mass spectrometry confirmed the putative caspase-7 cleavage site of pro–IL-1β, which was used to generate the 28-kDa fragment used for PBMC stimulation studies. Collectively, these results provide insight into the function of a poorly understood, processed 28-kDa form of IL-1β in patients with AIED that is uniquely generated by caspase-7 and is capable of activating further downstream proinflammatory cytokines. Further investigation may provide novel pharmacologic targets for the treatment of this rare disease.