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Am. J. Respir. Cell Mol. Biol., Volume 19, Number 2, August, 1998 259-268

Inhibition of TNF-alpha -induced NF-kappa B Activation and IL-8 Release in A549 Cells with the Proteasome Inhibitor MG-132

Michael A. Fiedler, Kara Wernke-Dollries, and James M. Stark

Division of Pulmonary Medicine, Children's Hospital Research Foundation, Cincinnati, Ohio

The working hypothesis of the studies described herein was that inhibition of proteasome-mediated Ikappa B degradation would inhibit TNF-alpha -induced nuclear factor-kappa B (NF-kappa B) activation, interleukin-8 (IL-8) gene transcription, and IL-8 protein release in A549 cells. Mutational analysis of the 5' flanking region of the IL-8 gene confirmed that an intact NF-kappa B site is necessary for TNF-alpha -induced IL-8 gene transcription. The addition of TNF-alpha to A549 cells resulted in rapid loss of Ikappa B from the cytoplasm of cells, associated with a corresponding increase in NF-kappa B-binding activity in nuclear extracts from the cells. However, pretreatment of the cells with the proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132, 10 µM) reversed the effects of TNF-alpha on IL-8 release from A549 cells (as determined with an enzyme-linked immunosorbent assay [ELISA]) and on IL-8 gene transcription (as determined with reporter-gene assays). MG-132 reversed the effects of TNF-alpha on Ikappa B degradation as determined by Western blot analysis. Ikappa B phosphorylation and ubiquination were not altered by MG-132, which implies that the effects of MG-132 were secondary to proteasome inhibition. MG-132 also reversed the increase in NF-kappa B binding in nuclear extracts from TNF-alpha -treated cells. These studies show that inhibition of proteasome-mediated Ikappa B degradation results in inhibition of TNF-alpha induced IL-8 production in A549 cells by limiting NF-kappa B-mediated gene transcription.




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Copyright © 1998 American Thoracic Society.