Chen Qingsheng, Rabach Lesley, Noble Paul, Zheng Tao, Lee Chun Geun, Homer Robert J, Elias Jack A
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
J Immunol. 2005 Feb 15;174(4):2305-13. doi: 10.4049/jimmunol.174.4.2305.
IL-13 is a major stimulator of inflammation and tissue remodeling at sites of Th2 inflammation. In Th2-dominant inflammatory disorders such as asthma, IL-11 is simultaneously induced. However, the relationship(s) between IL-11 and IL-13 in these responses has not been defined, and the role(s) of IL-11 in the genesis of the tissue effects of IL-13 has not been evaluated. We hypothesized that IL-11, signaling via the IL-11Ralpha-gp130 receptor complex, plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of IL-11, IL-11Ralpha, and gp130 in lungs from wild-type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of IL-11Ralpha on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Ralpha. They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11Ralpha loci and that these alterations are ameliorated in the absence of IL-11Ralpha. Lastly, they provide insight into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, matrix metalloproteinases, mucin genes, and gob-5 and stimulates and activates TGF-beta1 via IL-11Ralpha-dependent pathways. When viewed in combination, these studies demonstrate that IL-11Ralpha plays a key role in the pathogenesis of IL-13-induced inflammation and remodeling.
白细胞介素-13（IL-13）是Th2炎症部位炎症和组织重塑的主要刺激因子。在哮喘等以Th2为主导的炎症性疾病中，白细胞介素-11（IL-11）会同时被诱导产生。然而，在这些反应中IL-11与IL-13之间的关系尚未明确，且IL-11在IL-13组织效应发生过程中的作用也未得到评估。我们推测，通过IL-11Rα-gp130受体复合物进行信号传导的IL-11在IL-13诱导的组织反应中起关键作用。为了验证这一假设，我们比较了野生型小鼠和以肺特异性方式过表达IL-13的转基因小鼠肺中IL-11、IL-11Rα和gp130的表达。我们同时研究了IL-11Rα基因敲除对转基因IL-13组织效应的影响。这些研究表明，IL-13是IL-11和IL-11Rα的强效刺激因子。它们还表明，IL-13是具有野生型IL-11Rα基因座的小鼠炎症、纤维化、透明质酸积累、肌成纤维细胞积累、肺泡重塑、黏液化生以及呼吸衰竭和死亡的强效刺激因子，而在缺乏IL-11Rα时这些改变会得到改善。最后，这些研究通过证明IL-13通过依赖IL-11Rα的途径刺激CC趋化因子、基质金属蛋白酶、黏蛋白基因和gob-5，并刺激和激活转化生长因子-β1，从而深入了解了这些过程的机制。综合来看，这些研究表明IL-11Rα在IL-13诱导的炎症和重塑的发病机制中起关键作用。
