TNFα release from peripheral blood leukocytes depends on a CRM1-mediated nuclear export

Tumor necrosis factor-α (TNFα) 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 TNFα, and thus control of TNFα 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 TNFα release from LPS-stimulated human peripheral blood neutrophils and mononuclear cells. In addition, immunofluorescence confocal microscopy and immunoblotting analysis indicate that TNFα is localized in the nucleus of human neutrophils and mononuclear cells. This study demonstrates that the cellular release of TNFα from stimulated leukocytes is mediated by the CRM1-dependent nuclear export mechanism. Inhibition of CRM1-dependent cellular release of TNFα could thus provide a novel therapeutic approach for disorders involving excessive TNFα release.