Role of 5-lipoxygenase in IL-13-induced pulmonary inflammation and remodeling

Yun M. Shim, Zhou Zhu, Tao Zheng, Chun G. Lee, Robert J. Homer, Bing Ma, Jack A. Elias

Research output: Contribution to journalArticle

Abstract

Exaggerated levels of IL-13 and leukotriene (LT) pathway activation frequently coexist at sites of Th2 inflammation and in tissue fibrotic responses. However, the relationship(s) between the IL-13 and LTs in these responses have not been defined. We hypothesized that the 5-lipoxygenase (5-LO) pathway of LT metabolism plays an important role in the pathogenesis of IL-13-induced chronic inflammation and remodeling. To test this hypothesis, we evaluated the effects of IL-13 on components of the S-LO metabolic and activation pathways. We also compared the effects of transgenic IL-13 in C57BL/6 mice with wild-type and null 5-LO genetic loci. These studies demonstrate that IL-13 increases the levels of mRNA encoding cytosolic phospholipase A 2, LTA4 hydrolase, and 5-LO-activating protein without altering the expression of 5-LO, LTC4 synthase, LTB4 receptors 1 and 2, and cysteinyl-LT receptors 1 and 2. They also demonstrate that this activation is associated with the enhanced accumulation of LTB 4 but not of cysteinyl-LTs. Furthermore, they demonstrate that this stimulation plays a critical role in the pathogenesis of IL-13-induced inflammation, tissue fibrosis, and respiratory failure-induced death while inhibiting alveolar remodeling. Lastly, mechanistic insights are provided by demonstrating that IL-13-induced 5-LO activation is required for optimal stimulation and activation of TGF-ββ1 and the inhibition of matrix metalloproteinase-12. When viewed in combination, these studies demonstrate that 5-LO plays an important role in IL-13-induced inflammation and remodeling.

Original languageEnglish (US)
Pages (from-to)1918-1924
Number of pages7
JournalJournal of Immunology
Volume177
Issue number3
DOIs
StatePublished - Aug 1 2006

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Shim, Y. M., Zhu, Z., Zheng, T., Lee, C. G., Homer, R. J., Ma, B., & Elias, J. A. (2006). Role of 5-lipoxygenase in IL-13-induced pulmonary inflammation and remodeling. Journal of Immunology, 177(3), 1918-1924. https://doi.org/10.4049/jimmunol.177.3.1918