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Vol. 20, Issue 20, 4412-4423, October 15, 2009

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Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin 3 Expression

Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322

Submitted May 4, 2009; Revised July 29, 2009; Accepted August 18, 2009
Monitoring Editor: Karsten Weis

Expression of prohibitin 1 (PHB), a multifunctional protein in the cell, is decreased during inflammatory bowel disease (IBD). Little is known regarding the regulation and role of PHB during intestinal inflammation. We examined the effect of tumor necrosis factor alpha (TNF-), a cytokine that plays a central role in the pathogenesis of IBD, on PHB expression and the effect of sustained PHB expression on TNF- activation of nuclear factor-kappa B (NF-B) and epithelial barrier dysfunction, two hallmarks of intestinal inflammation. We show that TNF- decreased PHB protein and mRNA abundance in intestinal epithelial cells in vitro and in colon mucosa in vivo. Sustained expression of prohibitin in intestinal epithelial cells in vitro and in vivo (prohibitin transgenic mice, PHB TG) resulted in a marked decrease in TNF-–induced nuclear translocation of the NF-B protein p65, NF-B/DNA binding, and NF-B–mediated transcriptional activation despite robust IB- phosphorylation and degradation and increased cytosolic p65. Cells overexpressing PHB were protected from TNF-–induced increased epithelial permeability. Expression of importin 3, a protein involved in p50/p65 nuclear import, was decreased in cells overexpressing PHB and in colon mucosa of PHB TG mice. Restoration of importin 3 levels sustained NF-B activation by TNF- during PHB transfection. These results suggest that PHB inhibits NF-B nuclear translocation via a novel mechanism involving alteration of importin 3 levels. TNF- decreases PHB expression in intestinal epithelial cells and restoration of PHB expression in these cells can protect against the deleterious effects of TNF- and NF-B on barrier function.

Address correspondence to: Arianne L. Theiss (atheiss{at}emory.edu).

Abbreviations used: IBD, inflammatory bowel disease; NF-B, nuclear factor-kappa B; PHB, prohibitin; TNF-, tumor necrosis factor alpha

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