Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway
Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway
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DOI：
10.1172/jci200316815
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发表时间：
2003-08-01
影响因子：
15.9
通讯作者：
Elias, JA
中科院分区：
文献类型：
--
作者：
Blackburn, MR;Lee, CG;Elias, JA
IL-13是炎症和重塑的重要介质。我们假设腺苷积累、腺苷受体的改变和腺苷-IL-13自身诱导是IL-13诱导的病理学中的关键事件。为了测试这一点，我们表征了IL-13过表达对小鼠肺中腺苷、腺苷脱氨酶（ADA）活性和腺苷受体水平的影响。我们还确定了腺苷是否诱导ADA缺失小鼠肺中的IL-13。IL-13诱导炎症和重塑反应，导致呼吸衰竭和死亡。在此反应过程中，IL-13引起腺苷积累的进行性增加，抑制ADA活性和mRNA积累，并增加A（1）、A（2B）和A（3）腺苷受体的表达，但不增加A（2A）腺苷受体的表达。ADA酶治疗减少了IL-13诱导的腺苷增加，抑制了IL-13诱导的炎症、趋化因子产生、纤维化和肺泡破坏，并延长了IL-13转基因动物的生存期。此外，腺苷在ADA缺失小鼠中强烈诱导IL-13。这些发现表明腺苷和腺苷信号传导有助于并影响IL-13诱导的组织反应的严重性。他们还证明IL-13和腺苷在扩增途径中相互刺激，这可能有助于IL-13和/或Th 2介导的疾病的性质、严重程度、进展和/或慢性化。
IL-13 is an important mediator of inflammation and remodeling. We hypothesized that adenosine accumulation, alterations in adenosine receptors, and adenosine-IL-13 autoinduction are critical events in IL-13-induced pathologies. To test this, we characterized the effects of IL-13 overexpression on the levels of adenosine, adenosine deaminase (ADA) activity, and adenosine receptors in the murine lung. We also determined whether adenosine induced IL-13 in lungs from ADA-null mice. IL-13 induced an inflammatory and remodeling response that caused respiratory failure and death. During this response, IL-13 caused a progressive increase in adenosine accumulation, inhibited ADA activity and mRNA accumulation, and augmented the expression of the A(1), A(2B), and A(3) but not the A(2A) adenosine receptors. ADA enzyme therapy diminished the IL-13-induced increase in adenosine, inhibited IL-13-induced inflammation, chemokine elaboration, fibrosis, and alveolar destruction, and prolonged the survival of IL-13-transgenic animals. In addition, IL-13 was strongly induced by adenosine in ADA-null mice. These findings demonstrate that adenosine and adenosine signaling contribute to and influence the severity of IL-13-induced tissue responses. They also demonstrate that IL-13 and adenosine stimulate one another in an amplification pathway that may contribute to the nature, severity, progression, and/or chronicity of IL-13 and/or Th2-mediated disorders.