title: TNFalpha release from peripheral blood leukocytes depends on a CRM1-mediated nuclear export.
abstract: Tumor necrosis factor-alpha (TNFalpha) 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 TNFalpha, and thus control of TNFalpha 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 TNFalpha release from LPS-stimulated human peripheral blood neutrophils and mononuclear cells. In addition, immunofluorescence confocal microscopy and immunoblotting analysis indicate that TNFalpha is localized in the nucleus of human neutrophils and mononuclear cells. This study demonstrates that the cellular release of TNFalpha from stimulated leukocytes is mediated by the CRM1-dependent nuclear export mechanism. Inhibition of CRM1-dependent cellular release of TNFalpha could thus provide a novel therapeutic approach for disorders involving excessive TNFalpha release.
authors.affiliation: Department of Biology, St. John's University, NY 11439, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Miskolci
authors.forename: Chandra C
authors.initials: CC
authors.lastname: Ghosh
authors.forename: Janet
authors.initials: J
authors.lastname: Rollins
authors.forename: Carlos
authors.initials: C
authors.lastname: Romero
authors.forename: Hai-Yen
authors.initials: HY
authors.lastname: Vu
authors.forename: Staci
authors.initials: S
authors.lastname: Robinson
authors.forename: Dennis
authors.initials: D
authors.lastname: Davidson
authors.forename: Ivana
authors.initials: I
authors.lastname: Vancurova
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D028884:Karyopherins / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D005231:Fatty Acids, Unsaturated; D016209:Interleukin-8; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D000097606:Exportin 1 Protein; C038753:leptomycin B