Nature：新研究或可降低炎症药物副作用

犹他大学医学研究者们的新发现将从根本上改变关节炎等疾病的药物治疗。治疗炎症的现有药物往往会带来严重的副作用，即增加患者被病原体感染的风险，而这项新发现将有望把这种副作用降至最低。

领导这项研究的是犹他大学医学院副院长Y. Li教授，他指出这项发现为开发更安全的强力抗炎症药物提供了路线图，不仅为节炎患者还为其他数百万炎症相关疾病患者带来了福音，包括糖尿病、创伤性脑损伤和炎症性肠病等。“这将彻底改变相关领域的制药方式，”他说，“我们找到的制药新途径可以替换现有最有效的关节炎药物。此外，我们也为其他疾病中的炎症开辟了新治疗途径，之前人们因顾忌影响免疫系统而不敢尝试的治疗有望实现。”

这项由美国国立卫生研究院NIH资助的研究即将发表在11月11日的Nature网站上。犹他大学症准备通过与制药公司或USTAR机构合作，将这一技术商业化。Li教授指出这是一项惠及百万患者的成果，更是一场医药界的革新。

当我们的机体受到外伤或者感染时，就会释放细胞因子。这些蛋白进入细胞后发动三重攻击：杀死入侵者、激活免疫系统并引发炎症。炎症虽然能够对抗感染，但也会削弱血管引发副作用，导致关节、大脑或其他区域肿胀。长期以来，科学家们一直认为细胞因子仅通过一个细胞通路来应答感染，这意味着阻止细胞因子引发炎症的药物也会阻碍免疫系统及其杀死入侵者的能力。

现在，Li及其同事在小鼠研究中颠覆了上述老观点，他们发现细胞因子实际上是通过两个细胞通路来抵御感染：一个负责启动免疫系统并杀死入侵者，另一个则破坏组织和器官。发现这两个相互独立的通路对于药物研发有重大影响，“我们可以选择性阻断炎症通路而不会抑制患者的免疫系统，”Li说。“这完全改写了目前的制药策略。我们的研究主要针对关节炎，证实减少炎症和纤维化的新型药物将在这一领域大显身手。不过我们也相信，从心脏病后的纤维化到炎症性肠病等许多其他疾病也能够从我们的发现中受益。”

犹他大学专攻风湿病的内科医生助理教授Tracy M. Frech认为，这项发现对于风湿病领域有着巨大影响。“这一发现将会让我们能够更有效的治疗狼疮、系统性硬化病和一大类炎症性关节炎，而不会使患者更易受到感染，”她说，“这是一项显着的成果。”目前，研究人员正计划与制药公司或USTAR开展合作，大规模筛选可用于制药的化合物，以开发新一代抗炎症药物。

doi:10.1038/nature11603
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Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability

Weiquan Zhu, Nyall R. London, Christopher C. Gibson, Chadwick T. Davis, Zongzhong Tong, Lise K. Sorensen, Dallas S. Shi, Jinping Guo, Matthew C. P. Smith, Allie H. Grossmann, Kirk R. Thomas & Dean Y. Li

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment1, 2, 3, 4. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response5, 6. Paradoxically, the cytokines vital to a successful immune defence also have disruptive effects on endothelial cell–cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture7, 8, 9. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1β on endothelial stability in a human in vitro cell model are NF-κB independent and are instead the result of signalling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88–ARNO–ARF6 as a proximal IL-1β signalling pathway distinct from that mediated by NF-κB. Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.