Lautenberg Centre for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):E702-11. doi: 10.1073/pnas.1322691111. Epub 2014 Jan 27.
β-TrCP, the substrate recognition subunit of SCF-type ubiquitin ligases, is ubiquitously expressed from two distinct paralogs, targeting for degradation many regulatory proteins, among which is the NF-κB inhibitor IκB. To appreciate tissue-specific roles of β-TrCP, we studied the consequences of inducible ablation of three or all four alleles of the E3 in the mouse gut. The ablation resulted in mucositis, a destructive gut mucosal inflammation, which is a common complication of different cancer therapies and represents a major obstacle to successful chemoradiation therapy. We identified epithelial-derived IL-1β as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1β is induced by DNA damage via an NF-κB-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-κB, with failure to express the endogenous IL-1β receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1β prevents epithelial tight junction dysfunction and alleviates mucositis in β-TrCP-deficient mice. IL-1β antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.
β-TrCP 是 SCF 型泛素连接酶的底物识别亚基，它由两个不同的同源物广泛表达，可靶向降解许多调节蛋白，其中包括 NF-κB 抑制剂 IκB。为了了解 β-TrCP 在组织特异性中的作用，我们研究了在小鼠肠道中诱导性缺失 E3 的三个或全部四个等位基因的后果。这种缺失导致了黏膜炎，即一种破坏性的肠道黏膜炎症，这是多种癌症治疗的常见并发症，也是成功放化疗的主要障碍。我们发现上皮细胞衍生的 IL-1β 是黏膜炎发病的罪魁祸首，它诱导了黏膜屏障的破坏。令人惊讶的是，上皮细胞的 IL-1β 是通过一种非 NF-κB 依赖的机制，由 DNA 损伤诱导的。在没有 NF-κB 的情况下，肠道屏障破坏引起的组织损伤会加剧，并且在四个等位基因缺失时无法表达内源性的 IL-1β 受体拮抗剂 IL-1Ra。中和 IL-1β 的抗体可以防止上皮细胞紧密连接功能障碍，并缓解 β-TrCP 缺陷小鼠的黏膜炎。因此，应该考虑使用 IL-1β 拮抗剂来预防和治疗与黏膜炎相关的严重发病率。
