TNF{alpha} release from peripheral blood leukocytes depends on a CRM1-mediated nuclear export

Tumor necrosis factor-{alpha} (TNF{alpha}) is a potent pro-inflammatory cytokine that plays a major role in the pathogenesis of acute and chronic inflammatory disorders such as septic shock and arthritis, respectively. Leukocytes stimulated with inflammatory signals such as lipopolysaccharide (LPS)...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2006-12, Vol.351 (2)
Main Authors: Miskolci, Veronika, Department of Pediatrics, Feinstein Institute for Medical Research at the North Shore-Long Island Jewish Health System, New Hyde Park, NY 11040, Ghosh, Chandra C., Rollins, Janet, Romero, Carlos, Vu, Hai-Yen, Robinson, Staci, Davidson, Dennis, Vancurova, Ivana
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
INFLAMMATION
INHIBITION
MICROSCOPY
NEUTROPHILS
PATHOGENESIS
PROTEINS
RHEUMATIC DISEASES
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Summary:Tumor necrosis factor-{alpha} (TNF{alpha}) is a potent pro-inflammatory cytokine that plays a major role in the pathogenesis of acute and chronic inflammatory disorders such as septic shock and arthritis, respectively. Leukocytes stimulated with inflammatory signals such as lipopolysaccharide (LPS) are the predominant producers of TNF{alpha}, and thus control of TNF{alpha} release from stimulated leukocytes represents a potential therapeutic target. Here, we report that leptomycin B (LMB), a specific inhibitor of CRM1-dependent nuclear protein export, inhibits TNF{alpha} release from LPS-stimulated human peripheral blood neutrophils and mononuclear cells. In addition, immunofluorescence confocal microscopy and immunoblotting analysis indicate that TNF{alpha} is localized in the nucleus of human neutrophils and mononuclear cells. This study demonstrates that the cellular release of TNF{alpha} from stimulated leukocytes is mediated by the CRM1-dependent nuclear export mechanism. Inhibition of CRM1-dependent cellular release of TNF{alpha} could thus provide a novel therapeutic approach for disorders involving excessive TNF{alpha} release.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2006.10.045