Mechanism of tumour necrosis factor alpha mediated eosinophil survival

Vladislav Temkin, Francesca Levi-Schaffer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Prolonged eosinophil survival is an essential step in the late and chronic phases of allergic inflammation and is regulated by the eosinophil survival cytokines. Our work has demonstrated that tumour necrosis factor (TNF)-α enhances survival (Trypan blue exclusion test) of human peripheral blood eosinophils from mildly allergic patients in a dose-dependent manner. The survival activity of TNF-α was inhibited by anti-TNF-RI, anti-TNF-RII antagonist antibodies and anti-granulocyte-monocyte colony-stimulating factor (GM-CSF) neutralizing antibodies but not by anti-interleukin (IL)-3 or anti-IL-5 antibodies. Furthermore, TNF-α-induced GM-CSF release from eosinophils. Anti-TNF-α antibodies also inhibited GM-CSF release from eosinophils induced by rat mast cell sonicate, which enhances eosinophil survival. To define the signal transduction pathway involved in GM-CSF production, eosinophils were incubated either with various mitogen-activated protein kinases (MAPK) inhibitors (MEK, JNK, P38), or Cyclosporin A (calcineurin inhibitor), or MG-132 (proteasome inhibitor). Only the proteasome inhibitor significantly decreased both TNF-α-enhanced eosinophil survival (from 38.1 ± 4.1% to 13.3 ± 1.4%) and GM-CSF release (from 6.2 ± 0.7 pg/ml to 0.3 ± 0.1 pg/ml). TNF-α also induced nuclear factor-κB (NF-κB) translocation to the nucleus, an essential step in GM-CSF mRNA production. All these findings provide evidence that NF-κB is involved in TNF-α-enhanced eosinophil survival through the regulation of GM-CSF production by eosinophils.

Original languageAmerican English
Pages (from-to)20-26
Number of pages7
JournalCytokine
Volume15
Issue number1
DOIs
StatePublished - 7 Jul 2001

Bibliographical note

Funding Information:
This work was supported by a grant from the Aimwell Charitable Trust (London, UK). We are grateful to Professor Yinon Ben-Neriah for many helpful disscussions and and for providing anti-p65 antibodies. We thank Mark Tarshish for his excellent technical assistance with the confocal laser microscopy experiments, and we thank Madelyn Segev for her typing and editorial assistance.

Keywords

  • Eosinophils
  • GM-CSF
  • NF-κB
  • Survival
  • TNF-α

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