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Proteasome inhibitors modulate chemokine production in lung epithelial and monocytic cells

¹ Institute of Immunology, and ² Dept of Pneumology and Critical Care, Otto von Guericke University, Magdeburg, Germany

CORRESPONDENCE: A. Gerber, Institute of Immunology, Otto von Guericke University, Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany. Fax: 49 3916715852. E-mail: annegret.gerber,t;medizin.uni-magdeburg.de

Keywords: Interleukin-8, lung epithelial cell, monocytic cell, proteasome inhibitor

Received: July 9, 2003
Accepted March 8, 2004

This work was supported by the grant DKH 10-1355-Ge 1 from the Deutsche Krebshilfe.

Proteasome inhibition has become a target for antitumour and anti-inflammatory therapy. The present study investigated the influence of cysteine proteinase and proteasome inhibitors on chemokine production in lung epithelial cells and monocytic cells.

The lung carcinoma cell lines A549, SK-MES, NCI-H727, virus-transformed bronchial epithelial cell line BEAS-2B, primary lung epithelial cells, and the acute monocytic leukaemia cell lines Mono-Mac-6 and THP-1 were incubated with proteasome (N-acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN), ß-lactone) or cysteine proteinase inhibitor (L-trans-Epoxysuccinyl-Leu-3-methylbutylamide-ethyl ester) and the influence on chemokine production (interleukin-8: IL-8, monocyte chemoattractant protein-1, RANTES) was quantified at protein and mRNA levels.

Inhibition of proteasome activity by ALLN and ß-lactone resulted in significantly increased IL-8 secretion (5- to 22-fold). Cysteine proteinase inhibitors did not influence chemokine production. The simultaneous rise in IL-8 mRNA was caused by an increased half-life of mRNA and increased RNA synthesis. Moreover, analysis of transcription factor activation revealed induction of activator protein-1 (c-Jun) activity by proteasome inhibition, whereas nuclear factor-B (p50 and p65) was not activated. The significant increase in IL-8 production after proteasome inhibition was also observed in primary lung epithelial cells and in monocytic cells. In addition, the secreted IL-8 was biologically active as shown by the neutrophil chemotaxis assay.

In conclusion, it was shown that proteasome inhibitors stimulate interleukin-8 secretion in lung epithelial cells and monocytic cells, thus recruiting neutrophils.

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