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Published ahead of print on July 21, 2005, doi:10.1165/rcmb.2005-0069OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 5, November 2005, 483-489

A more recent version of this article appeared on November 1, 2005
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Submitted on February 16, 2005
Revised on July 21, 2005

Inhibition of TNF alpha-induced RANTES secretion by alkaline protease in A549 cells

Thomas M Krunkosky1*, Keishi Maruo2, Jan Potempa3, Carla L Jarrett1, and James Travis2

1 Department of Anatomy and Radiology, University of Georgia, Athens, GA, USA, 2 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA, 3 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA; Department of Microbiology, Jagiellonian University, Krakow, Poland

* To whom correspondence should be addressed. E-mail: tmkrunko{at}vet.uga.edu.

Pseudomonas aeruginosa is a gram-negative bacterium that is an opportunistic pathogen in cystic fibrosis patients and immunocompromised hosts. This bacterium produces a variety of proteolytic enzymes, including alkaline protease (AP), which has multiple biological effects. This study investigated the effects of AP on the A549 pulmonary epithelial cell line. Results demonstrate that AP inhibited TNF{alpha}-induced RANTES gene expression and secretion in a concentration-dependent manner. The TNF{alpha}-induced RANTES gene expression and secretion was attenuated with a neutralizing monoclonal antibody directed against the TNF receptor type 1 (TNFR1). Conversely, a neutralizing monoclonal antibody directed against TNF receptor type II had no effect, suggesting that these events were regulated through the TNFR1 receptor. Additionally, we observed that soluble TNF receptor type 1 (sTNFR1) levels were significantly increased in culture supernatants of AP-treated cells in a concentration-dependent manner. Lastly, membrane associated TNFR1 was decreased following AP exposures. In these studies, the enzymatically inactive form of AP had no effect on TNF{alpha}-induced RANTES secretion, shedding of sTNFR1, or membrane-associated TNFR1. These results demonstrate that AP stimulates shedding of cell-surface TNFR1, resulting in an increase in sTNFR1. Consequently, these events decrease the cells' ability to stimulate RANTES gene expression and secretion through TNFR1.






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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2005 American Thoracic Society. 		  New Orleans Int'l Conf