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

ABSTRACT: Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-? (TNF-?) on longevity of isolated human eosinophils. In contrast to Fas, TNF-? inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-? on eosinophil apoptosis was reversed by a TNF-? neutralising antibody. The anti-apoptotic effect of TNF-? 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-?. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-? induced phosphorylation and degradation of I?B and an increase in NF-?B DNA-binding activity. The survival-prolonging effect of TNF-? was reversed by inhibitors of NF-?B pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of I?B kinase, BMS-345541. TNF-? induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-? 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-? delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-?B and AP-1.

SUBMITTER: Kankaanranta H 

PROVIDER: S-EPMC3938678 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature