The rate of interleukin-1beta secretion in different myeloid cells varies with the extent of redox response to Toll-like receptor triggering.
The rate of interleukin-1beta secretion in different myeloid cells varies with the extent of redox response to Toll-like receptor triggering.
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不同髓样细胞中白介素-1Beta分泌的速率随氧化还原对Toll样受体触发的反应程度而变化。
DOI：
10.1074/jbc.m110.203398
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发表时间：
2011-08-05
期刊：
影响因子：
--
通讯作者：
Rubartelli A
中科院分区：
文献类型：
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作者：
Carta S;Tassi S;Pettinati I;Delfino L;Dinarello CA;Rubartelli A
人骨髓细胞激活NLRP 3炎性体并响应于各种Toll样受体（TLR）配体分泌白细胞介素（IL）-1β，但原代人单核细胞中的分泌速率远高于培养的巨噬细胞或THP-1细胞。不同的骨髓细胞在静息条件下也显示不同的氧化还原状态和对TLR活化的氧化还原反应。静息单核细胞显示平衡的氧化还原状态，具有低的活性氧（ROS）和抗氧化剂的产生。TLR参与诱导有效的氧化还原反应，增加ROS生成，随后是持续的抗氧化反应，同时伴有有效的IL-1β分泌。阻断ROS产生或抗氧化反应的药物阻止成熟IL-1β的分泌，但不阻止pro-IL-1β的生物合成，这表明氧化还原重构是IL-1β加工和释放的原因。与单核细胞不同，THP-1细胞和培养的巨噬细胞具有上调的抗氧化系统，其缓冲由TLR触发提供的氧化冲击并抑制随之发生的氧化还原反应。这种失败的氧化还原重塑被低效率的IL-1β加工和分泌所掩盖。高剂量（5 mm）的H2 O2克服了THP-1细胞的高抗氧化能力，恢复了有效的氧化还原反应，并增加了IL-1β分泌速率。这些数据一起表明，静息细胞中严格控制的氧化还原稳态是对TLR配体的稳健氧化还原应答的先决条件，而TLR配体又是有效的炎性小体活化所必需的。细菌DNA对炎性小体的激活不受氧化还原反应的调节，这表明IL-1β分泌的氧化还原依赖性调节仅限于一些炎性小体，包括NLRP 3，但不包括AIM-2。
Human myeloid cells activate the NLRP3 inflammasome and secrete interleukin (IL)-1β in response to various Toll-like receptor (TLR) ligands, but the rate of secretion is much higher in primary human monocytes than in cultured macrophages or THP-1 cells. The different myeloid cells also display different redox status under resting conditions and redox response to TLR activation. Resting monocytes display a balanced redox state, with low production of reactive oxygen species (ROS) and antioxidants. TLR engagement induces an effective redox response with increased ROS generation followed by a sustained antioxidant response, parallelled by efficient IL-1β secretion. Drugs blocking ROS production or the antioxidant response prevent the secretion of mature IL-1β but not the biosynthesis of pro-IL-1β, indicating that redox remodeling is responsible for IL-1β processing and release. Unlike monocytes, THP-1 cells and cultured macrophages have up-regulated antioxidant systems that buffer the oxidative hit provided by TLR triggering and suppress the consequent redox response. This aborted redox remodeling is paralleled by low efficiency IL-1β processing and secretion. High doses (5 mm) of H2O2 overcome the high antioxidant capacity of THP-1 cells, restore an efficient redox response, and increase the rate of IL-1β secretion. Together these data indicate that a tightly controlled redox homeostasis in resting cells is a prerequisite for a robust redox response to TLR ligands, in turn necessary for the efficient inflammasome activation. Inflammasome activation by bacterial DNA is not modulated by redox responses, suggesting that redox-dependent regulation of IL-1β secretion is restricted to some inflammasomes including NLRP3 but excluding AIM-2.