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Infection and Immunity, May 2005, p. 2766-2777, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2766-2777.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pneumocystis carinii Activates the NF-{kappa}B Signaling Pathway in Alveolar Epithelial Cells

Jing Wang,2 Francis Gigliotti,1,2 Sanjay Maggirwar,2 Carl Johnston,1 Jacob N. Finkelstein,1 and Terry W. Wright1,2*

Department of Pediatrics,1 Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 146422

Received 17 August 2004/ Returned for modification 10 September 2004/ Accepted 5 January 2005

Pneumocystis carinii pneumonia (PcP) is a clinically important infection of immunocompromised patients. Although the interaction of Pneumocystis with the alveolar epithelium has been well documented, very little information regarding the epithelial response to Pneumocystis is currently available. In order to study Pneumocystis-epithelium interactions, a murine cell line derived specifically from an alveolar epithelial cell (AEC) was utilized. The coculture of murine AECs with mouse Pneumocystis induced a dose- and time-dependent release of the CXC chemokine MIP-2. Importantly, the specific removal of Pneumocystis from the preparation, or the pretreatment of AECs with sulfasalazine, a potent and specific inhibitor of NF-{kappa}B, nearly completely abrogated the chemokine response to Pneumocystis. Since the murine MIP-2 promoter contains consensus {kappa}B binding sequences, the ability of Pneumocystis to stimulate NF-{kappa}B signaling in AECs was examined. Pneumocystis stimulation of an AEC line stably transfected with a {kappa}B-dependent reporter construct triggered the NF-{kappa}B signaling pathway and reporter production. These data were confirmed in gel shift assays, providing direct evidence that Pneumocystis induced the nuclear translocation of the p50/p65 heterodimeric form of NF-{kappa}B. Maximal NF-{kappa}B activation was dependent upon direct contact with viable Pneumocystis organisms. These data demonstrate that Pneumocystis activates NF-{kappa}B signaling in AECs and establish a reporter cell line for studying NF-{kappa}B activation in AECs. Given the global regulatory functions of the NF-{kappa}B family, these findings suggest that Pneumocystis directly alters AEC gene expression in a manner that promotes pulmonary immune and inflammatory responses.

* Corresponding author. Mailing address: Department of Pediatrics, P.O. Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. Phone: (585) 275-5944. Fax: (585) 756-7780. E-mail: Terry_Wright{at}urmc.rochester.edu.

Editor: T. R. Kozel

Infection and Immunity, May 2005, p. 2766-2777, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2766-2777.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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