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EXPORTIN 1 INHIBITION ATTENUATES NUCLEAR FACTOR-&kgr;B-DEPENDENT GENE EXPRESSION

Activation of nuclear factor (NF)-&kgr;B is mediated by signal-induced phosphorylation of I&kgr;B&agr;, subsequent I&kgr;B&agr; degradation, and then translocation of unbound NF-&kgr;B to the nucleus. Termination of gene expression occurs when I&kgr;B&agr; binds NF-&kgr;B subunits (Rel A) in the nucleus. Leptomycin B specifically inhibits export of I&kgr;B&agr; and the inactive I&kgr;B&agr;/Rel A complex via the nuclear export protein exportin 1. We hypothesized that inhibition of I&kgr;B&agr; nuclear export would increase nuclear I&kgr;B&agr; and attenuate NF-&kgr;B inflammatory gene expression in pulmonary microvascular endothelial cells. We found that inhibition of exportin 1 causes nuclear accumulation of both endogenous NF-&kgr;B (Rel A) and I&kgr;B&agr;. IL-1&bgr; causes nuclear accumulation of NF-&kgr;B (Rel A) but does not increase nuclear I&kgr;B&agr;. Inhibition of exportin 1 before IL-1&bgr; prevented an increase in the nuclear ratio of NF-&kgr;B (Rel A) to I&kgr;B&agr; and decreases NF-&kgr;B DNA binding. Furthermore, inhibition of exportin 1 attenuates IL-1&bgr;-induced phosphorylation of I&kgr;B&agr; without affecting I&kgr;B kinase phosphorylation. Lastly, inhibition of exportin 1 attenuates monocyte chemoattractant protein, IL-8, and intercellular adhesion molecule expression in response to IL-1&bgr; stimulation. We suggest that the decrease in cell activation due to exportin 1 inhibition is a result of termination of NF-&kgr;B DNA binding due to increased concentration of I&kgr;B&agr; in the nucleus.