title: Tumour necrosis factor-α regulates human eosinophil apoptosis via ligation of TNF-receptor 1 and balance between NF-κB and AP-1.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hannu
authors.initials: H
authors.lastname: Kankaanranta
authors.affiliation: The Immunopharmacology Research Group, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Pinja
authors.initials: P
authors.lastname: Ilmarinen
authors.affiliation: The Immunopharmacology Research Group, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Airway Disease Section, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: The Immunopharmacology Research Group, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Lahti
authors.affiliation: Airway Disease Section, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute of Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lindsay
authors.affiliation: The Immunopharmacology Research Group, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005912:Gliotoxin / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D011759:Pyrrolidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019014:fas Receptor / Q000494:pharmacology
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D000906:Antibodies; C491901:FAS protein, human; D007093:Imidazoles; D016328:NF-kappa B; D011759:Pyrrolidines; D011810:Quinoxalines; D047888:Receptors, Tumor Necrosis Factor, Type I; D012176:Retinoids; C106195:SR 11302; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C020972:pyrrolidine dithiocarbamic acid; D005912:Gliotoxin; D051550:I-kappa B Kinase