Inhibition of nuclear factor‐κB activation un‐masks the ability of TNF‐α to induce human eosinophil apoptosis

• Published in: European journal of immunology Vol. 32; no. 2; pp. 457 - 466
• Main Authors: Fujihara, Satoko, Ward, Carol, Dransfield, Ian, Hay, Ronald T., Uings, Iain J., Hayes, Brian, Farrow, Stuart N., Haslett, Christopher, Rossi, Adriano G.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag GmbH 01.02.2002
• Subjects: Apoptosis; Eosinophil; I^KB^a protein; Inflammation; IκBα; NF-^KB protein; NF‐κB
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200202)32:2<457::AID-IMMU457>3.0.CO;2-1

Apoptosis renders eosinophils functionally effete and marks them for ‘silent’ removal from inflamed sites by macrophages. We show, for the first time, that eosinophils exposed to TNF‐α rapidly lose their cytoplasmic levels of IκBα, the inhibitory subunit of NF‐κB. Consequently, TNF‐α triggers NF‐κB mobilization from the cytoplasm to the nucleus, as determined by tracking the NF‐κB subunit p65 by immunofluorescence and Western blot analysis. Inhibition of TNF‐α‐mediated IκBα degradation and NF‐κB activation by gliotoxin or the proteasome inhibitor MG‐132 un‐masks the caspase‐dependent pro‐apoptotic properties of TNF‐α. In addition, cycloheximide similarly renders TNF‐α pro‐apoptotic, suggesting that NF‐κB activation controls the production of a protein(s) that protects eosinophils from the cytotoxic effects of TNF‐α. Evidence is presented suggesting that TNF‐α triggered apoptosis is more susceptible to NF‐κB inhibition than constitutive apoptosis, leading to the possibility of the specific targeting of apoptosis in eosinophil sub‐populations. Prior to morphological signs of apoptosis, TNF‐α‐induced IL‐8 synthesis is abrogated by inhibition of NF‐κB. We propose that NF‐κB activation plays a critical role in controlling eosinophil responsiveness and apoptosis, and speculate that selective inhibitors of eosinophil NF‐κB activation may ultimately provide alternative therapeutic agents for the treatment of eosinophilic diseases, including asthma and allergic rhinitis.