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Leptomycin B Inhibits NFκB Activity in Stimulated Monocytic Cells by Increasing Nuclear Accumulation of IkBa
Author(s) -
Ghosh Chandra Chur,
Ramaswami Sitharam,
Vu HaiYen,
Juvekar Ashish P,
Vancurova Ivana
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.649.2
Subject(s) - nuclear export signal , nf κb , tumor necrosis factor alpha , lipopolysaccharide , nfkb1 , iκbα , transcription factor , thp1 cell line , microbiology and biotechnology , iκb kinase , cytokine , inflammation , biology , chemistry , signal transduction , cell nucleus , cell culture , biochemistry , immunology , gene , nucleus , genetics
Monocytic cells are the main producers of the pro‐inflammatory cytokine tumor necrosis factor alpha (TNFα). Synthesis of TNFα is regulated by the transcription factor NFκB, which is critically involved in numerous inflammatory disorders. We have previously shown that leptomycin B, an inhibitor of CRM1‐dependent nuclear export, inhibits the release of TNFα from stimulated monocytic U‐937 cells by inhibiting activity of NFκB. In this study, we investigated the mechanism by which LMB inhibits the NFκB activity in U‐937 cells stimulated with lipopolysaccharide (LPS), and peptidoglycan (PGN). We show that while LMB does not inhibit degradation of the NFκB inhibitor, IκBα, it induces IκBα nuclear accumulation in LPS and PGN‐stimulated monocytic cells, thus inhibiting NFκB DNA binding. Our results suggest that the increased nuclear accumulation of IκBα could be used as a therapeutic target for disorders characterized by high levels of NFκB activity and TNFα release.