Adenosine mediates IL-13–induced inflammation and remodeling in the lung and interacts in an IL-13–adenosine amplification pathway
Michael R. Blackburn, Chun G. Lee, Hays W.J. Young, Zhou Zhu, Janci L. Chunn, Min Jong Kang, Suman K. Banerjee, Jack A. Elias
Michael R. Blackburn, Chun G. Lee, Hays W.J. Young, Zhou Zhu, Janci L. Chunn, Min Jong Kang, Suman K. Banerjee, Jack A. Elias
View: Text | PDF
Article Immunology

Adenosine mediates IL-13–induced inflammation and remodeling in the lung and interacts in an IL-13–adenosine amplification pathway

Abstract

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 A1, A2B, and A3 but not the A2A 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.

Authors

Michael R. Blackburn, Chun G. Lee, Hays W.J. Young, Zhou Zhu, Janci L. Chunn, Min Jong Kang, Suman K. Banerjee, Jack A. Elias

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
ADA expression is decreased in lungs from IL-13 Tg mice. (a) Serum was c...
ADA expression is decreased in lungs from IL-13 Tg mice. (a) Serum was collected from 3-month-old wild-type, transgene-negative (–), or IL-13 Tg–positive (+) mice and subjected to zymogram analysis to examine levels of circulating ADA enzymatic activity. (b) ADA enzymatic activity was assessed in crude protein extracts from lungs from 3-month-old transgene-negative (–) and transgene-positive (+) mice using a zymographic assay system. Purine nucleoside phosphorylase (PNP) was used as a positive control for a purine metabolic enzyme that did not change. (c) ADA enzymatic activity was determined in lung extracts using a spectrophotometric assay. ADA-specific activities are shown and represent nanomoles of adenosine converted to inosine per minute per microgram of protein ± SE. n = 4 for each group. *P = 0.05 using Student t test. (d) Total cellular RNA was isolated from the lungs of 3-month-old transgene-negative (–) or transgene-positive (+) mice and subjected to RT-PCR using primers specific for ADA.