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PLoS One. 2014 Feb 28;9(2):e90298. doi: 10.1371/journal.pone.0090298. eCollection 2014.

Tumour necrosis factor-α regulates human eosinophil apoptosis via ligation of TNF-receptor 1 and balance between NF-κB and AP-1.

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The Immunopharmacology Research Group, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland ; Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland, and University of Tampere, Tampere, Finland.
The Immunopharmacology Research Group, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
Airway Disease Section, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
Department of Physiology & Pharmacology, Snyder Institute of Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.


Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.

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