5-/12-Lipoxygenase-linked cascade contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus promoting asthma development

Myungja Ro, A. Jin Lee, Jae-Hong Kim

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: As asthma progresses, the levels of IL-33 in serum are markedly increased and contribute to asthmatic development and exacerbation. Mast cells, one of the principal effector cells in the pathogenesis of asthma, express high levels of the IL-33 receptor ST2 and have been shown to be activated by IL-33. Thus, IL-33 stimulates mast cells to produce Th2-type cytokines such as IL-13, thus contributing to asthmatic development. However, the signaling mechanism for IL-33-induced synthesis of Th2 cytokines, particularly IL-13, has not been fully elucidated in mast cells. Methods: The role of 5- or 12-LO in the IL-33-induced synthesis of IL-13 was investigated using knockdown or pharmacological inhibitors in bone marrow-derived mast cells (BMMCs) and animal model. Results: Blockade of 5- or 12-LO significantly suppressed IL-33-induced synthesis of IL-13 in BMMCs. The subsequent action of 5- and 12-LO metabolites through their specific receptor, BLT2, was also critical for IL-33-induced synthesis of IL-13. We also demonstrated that the MyD88-p38 kinase cascade lies upstream of 5-/12-LO and that NF-κB lies downstream of 5-/12-LO to mediate the IL-33-induced synthesis of IL-13 in mast cells. Consistent with these findings, we observed that in an IL-33-administered asthmatic airway inflammation model, IL-13 levels were markedly increased in bronchoalveolar lavage fluid, but its levels were markedly suppressed by treatment with inhibitors of 5-LO, 12-LO or BLT2, further suggesting roles of 5-/12-LO in IL-33-induced IL-13 production. Conclusion: Our results suggest that "MyD88-5-/12-LO-BLT2-NF-κB" cascade significantly contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus potentially contributing to asthmatic development and exacerbation.

Original languageEnglish
JournalAllergy: European Journal of Allergy and Clinical Immunology
DOIs
Publication statusAccepted/In press - 2017 Jan 1

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Keywords

  • IL-13
  • IL-33
  • BLT2
  • Lipoxygenase
  • Mast cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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