ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules
ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules
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DOI：
10.1111/j.1365-2443.2004.00789.x
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发表时间：
2004-11-01
期刊：
影响因子：
2.1
通讯作者：
Taniguchi, S
中科院分区：
文献类型：
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作者：
Yamamoto, M;Yaginuma, K;Taniguchi, S
Toll样受体（TLR）通过与接头分子、髓样分化因子88（MyD 88）和/或含有TIR结构域的接头诱导IFN-β（Trif）结合来启动信号级联，以诱导用于微生物根除的各种促炎细胞因子。在用脂多糖（LPS）刺激TLR 4后，IL-1 β和IL-18都被加工，这取决于caspase-1的活化，尽管其机制尚不清楚。ASC是一种可能参与半胱氨酸天冬氨酸蛋白酶原-1活化的衔接蛋白。为了阐明ASC的需求，我们产生了Asc（-/-）小鼠。在用LPS刺激后，Asc（-/-）巨噬细胞在半胱氨酸天冬氨酸蛋白酶原-1的加工和pro-IL-1 β和pro-IL-18的成熟中失败，但正常产生其他促炎细胞因子，包括TNF-α和IL-6。MyD 88（-/-）和Trif（-/-）巨噬细胞显示出正常的caspase-1活化，证明MyD 88和Trif具有抑制作用。之后，LPS攻击的Asc（-/-）小鼠缺乏IL-1 β和IL-18的血清升高。Asc（-/-）小鼠无急性肝损伤和致死性休克。这些结果表明ASC在通过激活caspase-1释放IL-1 β/IL-18中的关键作用，并为宿主防御和疾病的炎症反应提供了新的见解。
Toll-like receptors (TLRs) initiate a signalling cascade via association with an adaptor molecule, myeloid differentiation factor 88 (MyD88) and/or TIR domain-containing adaptor inducing-IFN-beta (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1beta and IL-18 are processed, depending on the activation of caspase-1, although its mechanism remains unclear. ASC is an adapter protein possibly involved in the activation of procaspase-1. To unravel the requirement of ASC, we generated Asc(-/-) mice. Upon stimulation with LPS, Asc(-/-) macrophages failed in the processing of procaspase-1 and maturation of pro-IL-1beta and pro-IL-18, but normally produced other pro-inflammatory cytokines including TNF-alpha and IL-6. MyD88(-/-) and Trif(-/-) macrophages showed normal activation of caspase-1, demonstrating a dispensable role for MyD88 and Trif. After, LPS-challenged Asc(-/-) mice lacked serum elevation of IL-1beta and IL-18. Moreover, the Asc(-/-) mice exhibited neither acute liver injury nor lethal shock. These results demonstrate critical roles for ASC in the release of IL-1beta/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases.