Regulation of eosinophil apoptosis by nitric oxide: Role of c-Jun-N-terminal kinase and signal transducer and activator of transcription 5

Xianzhi Zhang, Eeva Moilanen, Aleksi Lahti, Mari Hämäläinen, Mark A. Giembycz, Peter J. Barnes, Mark A. Lindsay, Hannu Kankaanranta

Research output: Contribution to journalArticlepeer-review

50 Citations (SciVal)

Abstract

Background: Reduced eosinophil apoptosis is considered to be a key mechanism for eosinophilia in allergic diseases such as asthma, rhinitis, and eczema. Objective: The aim of our study was to investigate the possible modulatory effect of nitric oxide (NO) in human eosinophils. Methods: Apoptosis in isolated eosinophils was assessed by relative DNA fragmentation assay, annexin-V binding, and morphologic analysis. The activation of c-Jun-N-terminal kinase (JNK) and signal transducer and activator of transcription 5 (STAT5) was assessed by immunoblot analysis. Results: The NO donor S-nitroso-N-acetylpenicillamine (SNAP) reversed the survival-prolonging effect of IL-5 by inducing apoptosis. This effect was blocked by the NO scavenger (2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3oxide-potassium salt), indicating that reversal of IL-5-mediated eosinophil survival was due to NO. The effect of NO on IL-5-afforded cell survival was not mediated by cyclic guanosine 3′:5′-monophosphate (cGMP), because neither an inhibitor of guanylyl cyclase nor inhibitors of phosphodiesterases had any effect on SNAP-induced eosinophil apoptosis in IL-5-treated cells. SNAP induced a time-dependent increase in the activity of JNK, and an inhibitor peptide specific for JNK, L-JNKI1, completely reversed SNAP-induced apoptosis in IL-5-treated eosinophils. In contrast, SNAP did not inhibit IL-5-induced STAT5 activation. Inhibition of the activity of caspases by Z-Asp-CH2-DCB reversed the effect of SNAP, suggesting that NO promotes apoptosis in IL-5-treated human eosinophils in a caspase-dependent manner. However, this effect of NO was not mediated by means of activation of caspases 3, 8, or 9. Conclusions: Our results suggest that exogenous NO reverses IL-5-mediated eosinophil survival by inducing apoptosis, and this is mediated by means of activation of JNK in a cGMP-independent manner.

Original languageEnglish
Pages (from-to)93-101
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume112
Issue number1
DOIs
Publication statusPublished - 1 Jul 2003

Bibliographical note

Funding Information:
Supported by Jalmari and Rauha Ahokas Foundation (Finland), Tampere Tuberculosis Foundation (Finland), the Finnish Anti-tuberculosis Association Foundation (Finland), the Academy of Finland, and the Medical Research Fund of Tampere University Hospital (Finland).

Funding

Supported by Jalmari and Rauha Ahokas Foundation (Finland), Tampere Tuberculosis Foundation (Finland), the Finnish Anti-tuberculosis Association Foundation (Finland), the Academy of Finland, and the Medical Research Fund of Tampere University Hospital (Finland).

Keywords

  • Apoptosis
  • c-Jun-N-terminal kinase
  • Caspases
  • cGMP
  • Eosinophils
  • Nitric oxide
  • STAT5

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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