Lipoxin A4 counterregulates GM-CSF signaling in eosinophilic granulocytes

Vitaliy Starosta, Konrad Pazdrak, Istvan Boldogh, Tetyana Svider, Alexander Kurosky

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Eosinophils are granulated leukocytes that are involved in many inflammation-associated pathologies including airway inflammation in asthma. Resolution of eosinophilic inflammation and return to homeostasis is in part due to endogenous chemical mediators, for example, lipoxins, resolvins, and protectins. Lipoxins are endogenous eicosanoids that demonstrate antiinflammatory activity and are synthesized locally at sites of inflammation. In view of the importance of lipoxins (LXs) in resolving inflammation, we investigated the molecular basis of LXA4 action on eosinophilic granulocytes stimulated with GM-CSF employing the eosinophilic leukemia cell line EoL-1 as well as peripheral blood eosinophils. We report herein that LXA4 (1-100 nM) decreased protein tyrosine phosphorylation in EoL-1 cells stimulated with GM-CSF. Additionally, the expression of a number of GM-CSFinduced cytokines was inhibited by LXA4 in a dose-dependent manner. Furthermore, using a proteomics approach involving mass spectrometry and immunoblot analysis we identified 11 proteins that were tyrosine phosphorylated after GM-CSF stimulation and whose phosphorylation was significantly inhibited by LXA4 pretreatment. Included among these 11 proteins were α-fodrin (nonerythroid spectrin) and actin. Microscopic imaging showed that treatment of EoL-1 cells or blood eosinophils with GM-CSF resulted in the reorganization of actin and the translocation of α-fodrin from the cytoplasm to the plasma membrane. Importantly, α-fodrin translocation was prevented by LXA4 but actin reorganization was not. Thus, the mechanism of LXA4 action likely involves prevention of activation of eosinophilic granulocytes by GM-CSF through inhibition of protein tyrosine phosphorylation and modification of some cytoskeletal components.

Original languageEnglish (US)
Pages (from-to)8688-8699
Number of pages12
JournalJournal of Immunology
Volume181
Issue number12
DOIs
StatePublished - Dec 15 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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