Key Points IKIP inhibits NF-κB activation. IKIP inhibits IKKα/β phosphorylation. IKIP protects mice against LPS-induced septic shock and DSS-induced colitis. Stringent regulation of the transcription factor NF-κB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-κB activation. IKIP interacted with IKKα/β to block its association with NEMO, thereby inhibiting the phosphorylation of IKKα/β and the activation of NF-κB. Upon LPS, TNF-α, and IL-1β stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKα/β phosphorylation, IκB, and p65 phosphorylation and production of NF-κB–responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate–induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-κB activation by inhibition of IKKα/β phosphorylation through the disruption of IKK complex formation.

中文翻译：

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IKIP 通过抑制 IKKα/β 磷酸化负向调节 NF-κB 激活和炎症

关键点 IKIP 抑制 NF-κB 激活。IKIP 抑制 IKKα/β 磷酸化。IKIP 保护小鼠免受 LPS 诱导的感染性休克和 DSS 诱导的结肠炎。转录因子 NF-κB 信号传导的严格调控对于激活宿主免疫反应和维持体内平衡至关重要，但其严格调控所涉及的分子机制尚不完全清楚。在这项研究中，我们报告了 IKK 相互作用蛋白 (IKIP) 负向调节 NF-κB 激活。IKIP 与 IKKα/β 相互作用阻断其与 NEMO 的结合，从而抑制 IKKα/β 的磷酸化和 NF-κB 的激活。在 LPS、TNF-α 和 IL-1β 刺激下，IKIP 缺陷型巨噬细胞表现出更多和延长的 IKKα/β 磷酸化、IκB 和 p65 磷酸化以及 NF-κB 响应基因的产生。而且，IKIP 缺陷小鼠更容易受到 LPS 诱导的感染性休克和葡聚糖硫酸钠诱导的结肠炎的影响。我们的研究通过破坏 IKK 复合物的形成来抑制 IKKα/β 磷酸化，从而确定了 IKIP 在负调节 NF-κB 激活中的作用。